Consequences of psychophysiological stress on cytochrome P450-catalyzed drug metabolism.

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ARTICLE IN PRESS

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Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

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Consequences of psychophysiological stress on cytochrome P450-catalyzed drug metabolism

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Maria Konstandi a,∗ , Elizabeth O. Johnson b , Matti A. Lang c a b c

Department of Pharmacology, School of Medicine, University of Ioannina, Ioannina GR-451 10, Greece Department of Anatomy, University of Athens, School of Medicine, Mikras Asias 75, 11527 Athens, Greece National Research Centre for Environmental Toxicology, University of Queensland, Coopers Plains, Australia

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Article history: Received 30 January 2014 Received in revised form 17 April 2014 Accepted 18 May 2014

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Keywords: Stress Adrenergic receptor Glucocorticoids Drug metabolism Cytochrome P450s

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Contents

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Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a drug. Current evidence demonstrates a gene-, stress- and species-specific interference in stress-mediated regulation of genes encoding the major drug-metabolizing CYP isozymes. Stress-induced up-regulation of CYPs that metabolize the majority of prescribed drugs can result in their increased metabolism and consequently, in failure of pharmacotherapy. In contrast, stress-induced down-regulation of CYP isozymes, including CYP2E1 and CYP2B1/2, potentially reduces metabolism of several toxicants and specific drugs-substrates resulting in increased levels and altered toxicity. The primary stress effectors, the adrenergic receptor-linked pathways and glucocorticoids, play primary and distinct roles in stress-mediated regulation of CYPs. Evidence demonstrates that stress regulates major drug metabolizing CYP isozymes, suggesting that stress should be considered to ensure pharmacotherapy efficacy and minimize drug toxicity. A detailed understanding of the molecular events underlying the stress-dependent regulation of drug metabolizing CYPs is crucial both for the design of new drugs and for physiology-based pharmacokinetic and pharmacodynamic modeling. © 2014 Published by Elsevier Ltd.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The stress response system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug metabolism: role of cytochrome P450s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The stress response and cytochrome P450 isozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. CYP1A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. CYP2A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. CYP2B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. CYP2C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. CYP2D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Abbreviations: CYP, Cytochrome P450; PAH, polycyclic aromatic hydrocarbon; EROD, ethoxyresorufin 7-dealkylase; PROD, pentoxyresorufin 7-dealkylase; B[␣]P, benzo[␣]pyrene; PNP, p-nitrophenol hydroxylation; FMO, flavin-containing monoxygenases; EH, epoxide hydrolases; GST, glutathione S-transferases; UGT, UDP-glucuronosyltransferase; NAT, N-acetyltransferases; SULT, sulfotransferases; CES, carboxylesterase; Ahr, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; CRH, corticotropin-releasing hormone; LC, locus ceruleus; NE, norepinephrine; HPA, hypothalamo-pituitary adrenal axis; PVN, paraventricular nucleus; ARs, adrenergic receptors; beta-NF, beta-naphthoflavone. Q2 ∗ Corresponding author. Tel.: +30 2651007554; fax: +30 2651007859. E-mail address: [email protected] (M. Konstandi).

Stress is a constant factor in modern life and has become one of the most significant health problems in modern societies. The organism’s response to stress is a complex, multifactorial process that involves an elaborate neuroendocrine, cellular and molecular infrastructure. While it is well established that repeated or chronic stress can have deleterious effects on the health and well-being of individuals, the molecular mechanisms linking stress to disease initiation and progression are not fully understood. As such,

http://dx.doi.org/10.1016/j.neubiorev.2014.05.011 0149-7634/© 2014 Published by Elsevier Ltd.

Please cite this article in press as: Konstandi, M., et al., Consequences of psychophysiological stress on cytochrome P450-catalyzed drug metabolism. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.05.011

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4.6. CYP2E1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. CYP3A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. CYP2J5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stress-cytochrome P450 link: differential role of the primary stress response effectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Glucocorticoid regulation of cytochrome P450s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Adrenergic receptor-mediated regulation of cytochrome P450s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Consequences of chronic stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Diseases and cytochrome P450s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. Type-2 diabetes and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Immune disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.4. Cardiovascular diseases-metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.5. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.6. Stress-related choices in life-style . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Drug pharmacokinetics and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

investigations are currently focusing on dissecting the biological pathways linking stress and health. 44 Physiological response to stress is essentially mediated by the 45 hypothalamic–pituitary–adrenal (HPA) axis and the central and 46 peripheral components of the autonomic nervous system. The 47 integrity and precision of their interactions with other compo48 nents of the central nervous system are essential for mounting a 49 successful stress response. Chronic stress caused by exposure to 50 persistent or frequently repeated stressors induces a prolonged 51 activation of the stress response systems. The deleteriously over52 loaded system is faced with complications due to prolongation of 53 the adaptive response. In addition to the exquisitely orchestrated 54 adaptive response that challenges the homeostasis of the organ55 isms, stress also challenges the homeostasis and integrity of the 56 cell. A complex intra-cellular signaling network enables cells to 57 sense environmental changes and to adjust the cellular processes 58 including the bioenergetic, thermogenic and oxidative responses 59 accordingly, in order to re-establish homeostasis. For example, 60 chronic psychological stress is not only associated with a greater 61 risk for depression, but contributes to chronic diseases, such as 62 heart disease, obesity and infectious diseases (Chrousos and Gold, 63 1992; Chrousos and Kino, 2009; Johnson et al., 1992; Tsigos and 64 Chrousos, 2002). 65 Drug metabolism is one of the major factors contributing to 66 pharmacokinetics, in addition to absorption, distribution and elim67 ination. The major site of drug metabolism is the liver, and in 68 healthy individuals the metabolic processes are in homeosta69 sis. Drug metabolizing enzymes include both phase I, comprised 70 mainly of cytochromes P450 (CYPs) that catalyze oxidation reac71 tions, and phase II enzymes that catalyze conjugation reactions. 72 Modification of the hepatic signaling pathways will affect drug 73 metabolism and long-term disturbance of the metabolic pathways 74 can lead to intracellular accumulation of free radicals and other 75 metabolic products that are potentially toxic (Naik et al., 2013). 1 76Q3 It is well known that the expression of CYPs can be altered by 77 various diseases, including diabetes, obesity, depression, infections 78 and inflammation, all of which have been associated with chronic 79 stress (Arinc et al., 2005; Johnson et al., 1992; Konstandi et al., 2004; 80 Kotsovolou et al., 2010). 81 Stress can change the pharmacokinetic profile of a drug in 82 multiple ways. For example, stress can influence gastrointestinal 42 43

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Note: In the nomenclature of cytochromes, the human and rat genes are presented with capital letters in italics (e.g. CYP2E1). The corresponding murine gene is presented with small letters in italics (e.g. Cyp2e1). Proteins are presented with capital letters (e.g. CYP2E1).

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function and absorption, lipid distribution and blood flow, all known to be relevant to pharmacokinetics (Mangoni and Jackson, 2004). Stress can also increase the free fatty acid contents due to glucocorticoid-induced fat mobilization, which in turn, may displace drugs from albumin binding sites. In the circulatory system, serum albumin is an important carrier agent for both, free fatty acids and drugs, such as the antidiabetic sulfonylureas (i.e., acetohexamide, tolbutamide and gliclazide), which compete for the same binding sites on serum albumin (Anguizola et al., 2013). The reduced plasma protein drug-binding capacity can have serious consequences for pharmacokinetics, potentially resulting in sub-therapeutic or toxic levels of numerous drugs, such as oral anti-coagulants, beta-lactames, beta-blockers and calcium channel-blockers, among others (Pervanidou and Chrousos, 2012). In addition to these systemic effects, studies have shown that stress may alter the activity of the major drug-metabolizing enzymes in the liver, particularly the CYPs. The clinical significance of understanding the biological pathways linking stress to the regulation of cytochromes has spurred research in dissecting the differential roles of the two primary effectors of the stress response system, namely glucocorticoids and adrenergic pathways, on several signaling pathways regulating the expression of various CYP genes. This review summarizes the recent progress in our understanding on how stress activated signaling pathways can influence hepatic drug metabolism. Emphasis is given on the role of glucocorticoid- and adrenergic receptor-linked pathways in the regulation of CYPs. In our view, this information is crucial for a rational assessment of stress–drug interactions and for developing improved drug dosing algorithms for effective and safe pharmacotherapy. 2. The stress response system Stress has been defined as a state of threatened homeostasis caused by intrinsic or extrinsic adverse forces. This challenge to homeostasis is counteracted by a complex repertoire of physiologic and behavioral responses that aim to reestablish the threatened equilibrium of the organism. Although details of the pathways by which the brain translates stressful stimuli into an integrated biological response are incompletely understood, it is well-accepted that deregulation of these responses to stress can have severe consequences, and have been linked to the pathophysiology of various disorders (Chrousos, 2009; Johnson et al., 1992). Initially, exposure to stress stimulates the primary components of the stress response system located within the central nervous system. The central effectors of the stress system are tightly interconnected and include the hypothalamic hormones


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corticotropin-releasing hormone (CRH), arginine vasopressin, and pro-opiomelanocortin-derived peptides, as well as the locus ceruleus and autonomic norepinephrine (NE) centers in the brainstem. Anatomically, norepinephrine’s effect is facilitated via noradrenergic projections from the locus ceruleus and noradrenergic neurons in the A1 and A2 nuclei in the hindbrain to corticotropic releasing hormone (CRH) containing neurons in the paraventricular nucleus (PVN) of the hypothalamus (Bernardini et al., 1990). The effects of central NE appear to be mainly mediated by ␣2 adrenoceptors (ARs), which are expressed in high levels in most hypothalamic regions, particularly the PVN (Bird and Kuhar, 1977). The peripheral effectors of the stress response system include the pituitary–adrenal axis and the autonomic system, respectively; they are also functionally interconnected (Aguilera et al., 1988; File and Clarke, 1981). Peripheral adaptation aims to induce an appropriate response leading to the provision of essential energy sources to overcome the stressor, a process which entails a shift of energy substrates from storage sites to the bloodstream. The major end point effectors of the stress response (glucocorticoids, epinephrine and NE) on one hand, target the inhibition of glucose uptake, fatty acid storage and protein synthesis at storage sites, and on the other hand, stimulate the release of energy substrates, including glucose, free fatty acids and amino acids, from muscle, fat tissue and liver (Yates et al., 1980). These stress effectors also stimulate cardiovascular and pulmonary function, by increasing heart rate, blood pressure and respiration (Yates et al., 1980). The cascade of catabolic events is supplemented with suppression of several anabolic processes, such as digestion, growth, reproduction and immune function (Krieger, 1982). Containment of the stress response is crucial in order for the organism to avoid the detrimental consequences of prolonged activation of the stress response system (Krieger, 1982). As the prolonged activation of the catabolic processes are ultimately destructive and pathogenic, the pathophysiology of metabolic disturbances (myopathy, metabolic syndrome, fatigue, and glycemia alteration) and immunosuppression (increased susceptibility to infection and cancer), hypertension, growth retardation and tissue repair, peptic ulceration, as well as reproductive suppression (impotence and amenorrhea) have been attributed to chronic stress (Fig. 1) (Chida et al., 2006, 2007; Chrousos, 2009; Chrousos and Kino, 2009; Daskalopoulos et al., 2012a,b; Konstandi, 2013; Konstandi et al., 2004; Krieger, 1982; Swain, 2000; Tsigos and Chrousos, 2002; Vere et al., 2009).

3. Drug metabolism: role of cytochrome P450s Organisms have evolved a complex enzyme system to protect them against the consequences of exposure to toxic substances. Once a xenobiotic compound enters the body is recognized as a potential threat of the homeostasis and the detoxifying mechanisms of the body are activated. The hepatic xenobiotic metabolism plays a central role in this process, with the xenobiotic-sensing nuclear receptors (xenosensors), such as the pregnane X receptor (PXR), aromatic hydrocarbon receptor (AhR) and constitutive androstane receptor (CAR), holding essential roles in the regulation of the major xenobiotic (drug)-metabolizing CYPs (Handschin and Meyer, 2003). The aim is the conversion of the foreign compound, usually to an inactive product, that can be subsequently and readily excreted from the body via urine or bile following conjugation with endogenous substrates. These enzymatic reactions are aimed at increasing the water solubility of the compound, thus making it easier to excrete. Typically, the enzymatic reactions take place in two phases. In Phase I, foreign compounds, including drugs, chemical carcinogens and toxicants, are metabolized through various oxidation reactions to increase their water

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Fig. 1. Schematic of the neuroendocrine response to stress that presumably affects the regulation of drug-metabolizing CYPs. In the periphery, epinephrine/norepinephrine bind to adrenergic receptors (AR) on hepatocytes, immune cells (stimulate release of cytokines), blood vessels (modify liver hemodynamics) and on pancreatic ␤-cells (control insulin release positively via ˇ2 -ARs or negatively via ˛2 -AR). In the hypothalamus, norepinephrine controls the release of several releasing factors that regulate the secretion of hormones from the pituitary (Konstandi, 2013). The left side of the scheme indicates the effect of hypothalamic–pituitary–adrenal axis. CRH: corticotropin releasing hormone; GHRH: growth hormone releasing hormone; TRH: thyrotropin releasing hormone; TSH: thyrotropin stimulating hormone; GH: growth hormone; T3, T4: thyro hormones; ACTH: adrenocorticotropin hormone; IR: insulin receptor; CytR: cytokine receptor; GHR: growth hormone receptor; TR: thyroid hormone receptor; GR: glucocorticoid receptor.

solubility. In addition, a functional group (e.g. hydroxyl group) is added in the foreign molecule, to prepare it for the subsequent phase. During Phase II the metabolic products of Phase I are conjugated with endogenous molecules, such as glucuronic acid, glutathione or sulphate groups, and form complexes that are highly soluble in water. Conjugation with acetyl groups is also a possibility (Gonzalez, 2005). The main families of enzymes that are involved in the Phase I include cytochrome P450s (CYPs), flavincontaining monoxygenases (FMO) and epoxide hydrolases (EH). Those involved in Phase II include, glutathione S-transferases (GST), UDP-glucuronosyltransferases (UGTs), N-acetyltransferases (NAT) and sulfotransferases (SULT) (Gonzalez, 2005). While these enzymatic systems are designed to metabolize and eliminate the xenobiotic compound, under certain circumstances and depending on the structure of the compound, xenobiotic biotransformation may lead to the formation of biologically reactive molecules with serious toxic effects including, cell death, carcinogenicity, teratogenesis, oxidative stress and other toxic manifestations (Cribb et al., 2005; Gonzalez, 2005; Gonzalez and Gelboin, 1994; Gonzalez and Yu, 2006; Guengerich, 2003; Ingelman-Sundberg, 2004a; Xu et al., 2005). Taken together, the outcomes of biotransformation potentially include: (1) formation of inactive metabolites (the most common), (2) formation of toxic metabolites and (3) formation of an active drug from a pro-drug (Chen et al., 2004; Gonzalez, 2005). In this later case, an inactive compound is converted into pharmacologically active forms through CYP-catalyzed metabolism. Given the unlimited number and amounts of xenobiotics encountered constantly by living organisms, metabolizing enzymes are faced with two essential challenges. First, they need to recognize and metabolize all the different xenobiotic structures with a reasonable efficiency.


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Secondly, their activity needs to be adjustable according to fluctuating concentrations of the chemicals entering the body (du Souich and Fradette, 2011; Nebert et al., 2013; Pelkonen et al., 2008). The first challenge is partially resolved by the evolution of multiple gene families encoding for drug metabolizing enzymes, each of which consists of several members (Nebert, 2000; Nebert and Russell, 2002; Nebert et al., 2013; Nelson et al., 1993). As a result, living organisms are armored with numerous enzymes that have distinct, yet partially overlapping substrate specificities. These enzymes can metabolize, albeit with variable efficiencies, various xenobiotics entering the body. The gene families encoding for drug metabolizing enzymes comprise the fastest evolving gene system after the immunoglobulin genes, a property related to the critical need to recognize and eliminate new chemical structures. This is of particular significance when a species migrates or is installed into a new habitat (Nebert, 2000; Nebert and Russell, 2002; Nebert et al., 2013; Nelson et al., 1993). The second challenge of adjusting for fluctuating concentrations that is faced by an organism’s metabolic system, is met by the advanced cellular signaling system that regulates the level of expression of drug metabolizing enzymes in various sites within the body. A series of xenobiotic recognizing receptors acting as transcription factors has evolved. These proteins are activated upon ligand binding and migrate to the nucleus from the cytoplasm, thus activating the enzyme coding genes by interacting with the regulatory elements at the respective promoters. It is essential for the enzyme system that those xenobiotics activating the regulatory transcription factors can also serve as substrates for the induced enzymes. Thus, this self-regulatory system can adjust its activity level according to the amounts of xenobiotics entering the cells. Like enzymes, xenobiotic-activated transcription factors can also recognize and be activated by many compounds (Daskalopoulos et al., 2012a; Hay, 2011; Konstandi et al., 2013; Nebert, 2000; Zhou et al., 2009a). Cytochrome P450s constitute the major drugmetabolizing enzyme system of metabolic phase I and is found in a wide variety of living organisms (Table 1) (Danielson, 2002; Nelson, 2009; Sigel et al., 2007). Although CYPs are mainly expressed in the endoplasmic reticulum of the liver, they are also found in the vast majority of other mammalian tissues and account for about 75% of metabolic reactions (Guengerich, 2008). Members of families 1–3 (Table 1) catalyze the metabolism of numerous and diverse endogenous and exogenous substrates including drugs, chemical carcinogens, pre-carcinogens, food additives, steroid hormones, prostaglandins, fatty acids, biogenic amines, lipid hydroperoxides, environmental pollutants and a plethora of other xenobiotics (Gonzalez, 1988, 2005; Gonzalez and Gelboin, 1994; Guengerich, 2003). Several CYP isoforms are also highly expressed in several specific tissues, such as the small intestine or olfactory mucosa, suggesting tissue-specific roles (Guengerich, 2008). The bioactivation of several substances to form active compounds, including highly reactive free-radicals, arylating or alkylating intermediates has frequently been attributed to cytochrome P450s (Guengerich, 2008; Hollenberg, 1992). Although these active compounds are usually excreted from the body following detoxification (Gonzalez, 1988), there are times when the oxygenation reaction products attack cellular biomolecules, such as DNA, RNA, proteins and lipids triggering mutations, as well as cell transformation, or even cell death. The fact that these processes are tied to tumor initiation and progression along with various toxic manifestations (Gonzalez, 1988; Hollenberg, 1992) underscores the necessity for a thorough examination of the multiplicity, substrate specificities and regulation of the various CYPs. The liver is a sexually dimorphic organ, where various plasma proteins, receptors, cellular signaling pathways, metabolic enzymes, including cytochrome P450s, demonstrate characteristic sex differences in their expression profile. The sexual

dimorphism in liver CYP genes is regulated at the transcription level by the temporal pattern of plasma growth hormone (GH) secretion (Legraverend et al., 1992; Wiwi and Waxman, 2004). Intermittent plasma GH pulses, typical in adult male rats, stimulate hepatic CYP2C11 expression and inhibit CYP2E1 (Waxman et al., 1991). Continuous exposure to GH, a condition mimicking the adult female GH secretion profile, induces the expression of the female CYP isoforms, such as CYP2C12 (Table 1), but inhibits the expression of the male-specific isoforms, CYP2C11, CYP2A2 and CYP4A2 (Pampori and Shapiro, 1999; Wiwi and Waxman, 2004). Inter-individual variability in drug response and adverse reactions, as well as in the susceptibility to chemical carcinogens and other toxic substances has been attributed, at least in part, to the polymorphic nature of various CYP isoforms (Pelkonen and Raunio, 1997). The distribution of the common variant alleles of CYP genes also varies among different ethnic populations; this may explain the differential drug efficacy and toxicity observed in distinct populations (Ingelman-Sundberg et al., 2007; Stranger et al., 2007). At present, more than 350 functionally different CYP alleles have been identified (Ingelman-Sundberg et al., 2007). The extensive polymorphism of CYP1A1, CYP2A6, CYP2A13, CYP2C8, CYP2D6, CYP3A4 and CYP3A5 is believed to have significant impact on the fate of therapeutic drugs.

4. The stress response and cytochrome P450 isozymes In addition to activation of the HPA axis and the central and peripheral catecholaminergic systems, stress affects various systems and signaling pathways that control other vital functions of the body (Chrousos, 2009; Chrousos and Kino, 2009; Tsigos and Chrousos, 2002). Relevant to drug metabolism are changes induced in the secretion of thyroid and growth hormones that are regulators of several CYPs (Fig. 1) (Daskalopoulos et al., 2012a; Liddle et al., 1998; Ram and Waxman, 1991; Takahashi et al., 2010). Activation of the HPA axis by stress is followed by suppression of hypothalamic–pituitary–thyroid axis (Helmreich and Tylee, 2011), inhibiting the conversion of T4 (inactive hormone) to T3 (active hormone). Somatostatin participates in this down-regulating effect. Stress stimulates the secretion of somatostatin, which inhibits both, TRH and TSH release (Fig. 1) (Charmandari et al., 2003). The CRH triggered release of somatostatin appears also to mediate the stress-induced suppression of GH secretion (Charmandari et al., 2003). This effect results in the down-regulation of the insulin-like growth factor-1 (IGF-1) activity, which is a critical parameter in the insulin-mediated regulation of various CYPs (Kim and Novak, 2007). STAT5b, a GH-pulse-activated transcription factor that usually acts in concert with the HNF4␣, is a positive regulator of various CYPs in the liver (Fig. 2) (Guengerich, 2003; Ram and Waxman, 1991; Waxman and Holloway, 2009; Wiwi and Waxman, 2004), including the CYP3A4 (Flierl et al., 2008), CYP2C and CYP2D genes (Ram and Waxman, 1991; Waxman and Holloway, 2009; Waxman et al., 1991; Wiwi and Waxman, 2004). Besides the HNF4␣, some other HNFs, may also act as co-activators with the STAT5b (Wiwi and Waxman, 2004). The catecholaminergic system appears to regulate GH secretion: stimulation of adrenergic receptors inhibits hypothalamic release of GH-releasing hormone (GHRH) and GH secretion from the pituitary, resulting in suppression of STAT5b activation (Fig. 2) (McMahon et al., 2001; Tsigos and Chrousos, 2002; Tuomisto and Mannisto, 1985). Insulin exerts a potent negative regulation on CYP2E1, CYP3A, CYP2C and CYP2D mainly via activation of PI3K/AKT/FOXO1 signaling pathway (Fig. 3) (Daskalopoulos et al., 2012a; Kim and Novak, 2007; Woodcroft et al., 2002). During psychological stress, insulin acts competitively with the stress hormones. However, in some cases, exposure to repeated or chronic stress, may lead to insulin


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Table 1 The major drug metabolizing CYP isozymes in humans and other animal species. CYP family

CYP1

CYP subfamily

Monkey

Rat

Mouse

CYP1A1 CYP1A2 CYP1B1




CYP2A

CYP2A6 CYP2A7 CYP2A13

CYP2A23 CYP2A24

CYP2A1 CYP2A2 CYP2A3

CYP2B

CYP2B6 CYP2B7

CYP2B17

CYP2C

CYP2C8 CYP2C9 CYP2C18 CYP2C19

CYP2C20 CYP2C43

CYP2B1 CYP2B2 CYP2B3 CYP2C6 CYP2C7a CYP2C11a CYP2C12a CYP2C13a CYP2C22 CYP2C23

CYP2A4 CYP2A5 CYP2A12 CYP2A22 CYP2B9 CYP2B10

CYP2D

CYP2D6 CYP2D7 CYP2D8

CYP2D17b CYP2D19b CYP2D29b CYP2D30b CYP2D42b

CYP2D1 CYP2D2 CYP2D3 CYP2D4 CYP2D5 CYP2D18

CYP2E

CYP2E1

CYP2E1

CYP2E1

CYP3A

CYP3A4 CYP3A5 CYP3A7 CYP3A43

CYP3A8

CYP3A1/23 CYP3A2a CYP3A9a CYP3A18a CYP3A62

CYP1A CYP1B

CYP2

CYP3

a b

CYP isozyme Human

364

365

4.1. CYP1A

352 353 354 355 356 357 358 359 360 361 362 363

366 367 368 369 370 371 372 373 374 375 376

CYP3A11 CYP3A13 CYP3A16 CYP3A25 CYP3A41 CYP3A44

Indicates a sex-specific CYP isozyme. Indicates a strain-specific CYP isozyme; (Martignoni et al., 2006).

resistance, and the resulting changes in insulin levels may drastically affect the regulation of various CYPs (Woodcroft and Novak, 1997). The role of pro-inflammatory cytokines in CYP regulation is well established. Several studies have shown that they downregulate CYP3A and CYP2C expression (Barclay et al., 1999; Johnson et al., 1992; Liu et al., 2005; Mealy et al., 1996; Nelson, 2009; Spatzenegger and Jaeger, 1995). Stress induces the release of epinephrine/norepinephrine from the adrenal medulla, which in turn activates alpha- and beta-ARs that are expressed on the immune cells thus promoting the secretion of a number of cytokines and other immune factors including TNF␣, IL-1 and IL-6 (Fig. 1) (El-Sankary et al., 2000; Ellenbroek et al., 1998; Exton, 1985; Flierl et al., 2007; Pervanidou et al., 2008).

351

CYP2C29 CYP2C37 CYP2C38 CYP2C39 CYP2C40 CYP2C44 CYP2C50 CYP2C54 CYP2C55 CYP2D9 CYP2D10 CYP2D11 CYP2D12 CYP2D13 CYP2D22 CYP2D26 CYP2D34 CYP2D40 CYP2E1

CYP1A1 and CYP1A2 are members of the CYP1A subfamily (Table 1) (Dipple, 1983; Sugimura and Sato, 1983). Whereas, CYP1A1 is typically an extrahepatic enzyme (Choudhary et al., 2005; Guengerich, 1997; Martignoni et al., 2004; Shimada et al., 1997), CYP1A2 is mainly expressed in the liver of humans and several other species (Table 1) (Choudhary et al., 2005; Shimada et al., 1997). CYP1A1 and CYP1A2 metabolize several environmental pollutants and carcinogens. Aromatic amines are primarily bioactivated by CYP1A2, and polycyclic aromatic hydrocarbons (PAHs) by both CYP1A isozymes. Notably, PAHs also induce these cytochromes (Kawajiri, 1999; Pasanen and Pelkonen, 1994). For

example, benzo[␣]pyrene, one of the major PAH components in coal tar, cigarette smoke, diesel exhaust condensate and heavily cooked food, induces CYP1A1, and acts as its substrate (Cheng and Morgan, 2001). CYP1A2 shares several substrates with the CYP1A1, and catalyzes the metabolism of about 5% of the prescribed drugs (Kawajiri, 1999; Zhang et al., 1999). Both, CYP1A1 and CYP1A2 genes, are regulated at transcriptional level by the AhR, which forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT). The formed complex, interacts with upstream enhancer elements (XREs), at the CYP1A1 and CYP1A2 promoters causing induction (Nebert, 2000; Okey, 1990). Many CYP1A substrates act as ligands of the AhR inducing these isozymes. These include several drugs, such as omeprazole and rifampicin, as well as the compound betanaphthoflavone (Martignoni et al., 2004; Roymans et al., 2005), PAHs, polychlorinated biphenyls (PCBs) and other environmental toxicants (Shou et al., 1996). Inhibition of these isozymes can result in reduced metabolism of drug-substrates and pre-carcinogens (inactive carcinogens that require metabolic conversion into reactive carcinogens) (Kawajiri, 1999; Mulder, 1994; Shou et al., 1996). For example ketoconazole inhibits CYP1A1 and furafylline inhibits CYP1A2, whereas alpha-naphthoflavone inhibits both CYP isozymes (Kobayashi et al., 2003; Newton et al., 1995; Shimada et al., 1998). Stress has been found to alter both, constitutive and B[␣]Pinduced CYP1A1/2 expression (Table 2). The effects of stress on CYP1A regulation appear to be stress-specific and species-specific (Daskalopoulos et al., 2012a; Jorgensen et al., 2001; Konstandi


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M. Konstandi et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx EROD: CYP1A1-catalyzed ethoxyresorufin 7-deethylation (indicates CYP1A1 activity); PROD: CYP2B1/2-catalyzed pentoxyresorufin 7-depentylation (indicates CYP2B1/2 activity); PNP: CYP2E1-catalyzed p-nitrophenol hydroxylation (indicates CYP2E1 activity); MDS: early maternal deprivation stress; RS: repeated restraint stress; RHS: repeated handling stress; IS: immobilization stress; MS: mild unpredictable stress; *yr: only in young rats, not in adults; ** glucocorticoids induce CYP2C at low concentration and inhibit it at high concentration; BP: benzo[␣]pyrene; r: rat; m: murine; ach: Arctic charr; f: fish; pbl: peripheral blood lymphocytes; hpec: human pulmonary epithelial cells; AR: adrenergic receptor; Epinephrine: peripheral ␤1/2 -agonist with lower affinity for alpha-ARs; Peripheral stimulation: Phenylephrine (␣1 -agonist) or epinephrine-induced stimulation of peripheral ARs. Stimulation: central and peripheral stimulation of ARs; Central blockade: Prazosin-induced inhibition of ␣1 -ARs in the central nervous system; H. stimulation: Direct stimulation of hepatocyte ARs with specific agonists; Black arrows indicate strong effect, whereas the gray arrows indicate a weak effect.

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Table 2 Summarized presentation of the main effects of stress and stress response effectors on CYP expression.



Fig. 2. The signaling pathways mediating the effects of growth hormone (GH) and glucocorticoids on CYP regulation. Upon the stress-induced GH activation (stress stimulates norepinephrine release in the hypothalamus that positively controls GHRH release and finally GH secretion from the pituitary), the hormone binding to GHR activates the GHR-associated tyrosine kinase JAK2, which in turn tyrosine phosphorylates the cytoplasmic domain of GHR at multiple sites, generating docking sites for STAT5b and other SH2 domain-containing proteins. STAT5b binds to a subset of these sites via its SH2 domain and then undergoes JAK2-catalyzed tyrosine phosphorylation, followed by STAT5b dimerization, nuclear translocation and induced transcription of target genes. Phosphotyrosine phosphatase(s) (PTPase) deactivate STAT5b, which may then be reactivated in a subsequent cycle of GHR-JAK2-catalyzed tyrosine phosphorylation. In males, this STAT5b cycle functions in response to a single male GH pulse before signaling from GHR to STAT5b is terminated, but in females it is much less robust, and is more rapidly terminated in cells exposed to a femalelike (continuous) GH pattern (Waxman et al., 1991; Wiwi and Waxman, 2004). On the other hand, glucocorticoid receptor (GR) activates hepatic gene expression by two different modes of action: (1) the ‘classical’ mode depends on direct interaction with a glucocorticoid response element on DNA in target gene promoters. (2) The glucocorticoid-GR complex functions as a coactivator for STAT5 that has been activated by growth hormone signaling without direct GR binding on DNA.

405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429

et al., 2004). While repeated restraint stress decreased basal CYP1Acatalyzed ethoxyresorufin 7-dealkylase (EROD) activity in the rat liver, repeated mild unpredictable stress increased it. On the other hand, restraint stress up-regulated constitutive Cyp1a2 expression in the murine liver (Flint et al., 2010), and markedly stimulated CYP1A1/2 inducibility by PAHs in the rat and murine liver. Mild unpredictable stress had only a weak effect (Flint et al., 2010; Konstandi et al., 2004, 2005). Down-regulation of CYP1A1 inducibility by B[␣]P in the rat liver following restraint stress has also been reported (Konstandi et al., 2004). Repeated handling stress repressed B[␣]P-induced CYP1A expression in the liver of Arctic charr (Salvelinus alpinus), although this finding is not compatible with a previous report showing a corticosterone-mediated increase in B[␣]P-induced CYP1A expression in cultured fish hepatocytes (Jorgensen et al., 2001). Differences in CYP1A responses to specific types of psychological stress may be related, in part, to a differential neurobiological state induced by each specific stress paradigm. Species-specificity in the stress-induced CYP1A changes may be associated with the species-related neurochemical, neuroendocrine, behavioral and other physiological differences observed following stress, including the species-specific differential sensitivity to stress stimuli (Boissy, 1995; Cure and Rolinat, 1992; Konstandi et al., 2000b; Prasad et al., 1995; Spanagel et al., 1995). Furthermore, differential effects of stress may further be confounded by the fact that even the same

7

Fig. 3. The insulin/PI3K/AKT/FOXO1 signaling pathway in the stress- and ARinduced CYP regulation. The stress-induced epinephrine release from adrenal medulla stimulates ␤2 -ARs on pancreatic beta-cells and enhances the release of insulin in response to increased plasma glucose levels (Woodcroft and Novak, 1997). In turn, insulin stimulates insulin receptors (IR) in hepatocyte plasma membranes and this effect results in the phosphorylation of the insulin receptor substrate (IRS) at different docking sites where the phosphatidylinositol 3-kinase (PI3K) binds. Phosphorylated PI3K converts phosphatidylinositol biphosphate (PIP2) to phosphatidylinositol triphosphate (PIP3), which in turn activates protein kinase B (AKT). Upon activation AKT phosphorylates the transcription factor forkhead box O1 (FOXO1) that subsequently translocates into the cytoplasm thus terminating CYP gene transcription. The stress-activated c-Jun N-terminal kinases (JNK) phosphorylate FOXO1 in the cytoplasm thus promoting the nuclear localization of FOXO1, thus counteracting the effect of AKT. The final outcome on gene regulation depends on the interplay between AKT and JNK (Daskalopoulos et al., 2012a; Hay, 2011).

individual may respond to the same stressful event differently according to various intrinsic and extrinsic conditions that prevail the specific period of time. 4.2. CYP2A The major human CYP2A isoforms are CYP2A6, CYP2A7 and CYP2A13 (Table 1) (Martignoni et al., 2006). CYP2A isozymes are also expressed in other animal species (Table 1) and are inducible by a number of diverse agents, such as phenobarbital, pyrazole, rifampicin, dexamethasone, nicotine, ethanol, smoking and cocaine (Konstandi, 1996; Martignoni et al., 2006; Pelkonen et al., 2000; Robottom-Ferreira et al., 2003). CYP2A6 accounts for about 5–10% of the total hepatic CYP content, and its substrates include coumarin, nicotine, cyclophosphamide, as well as aflatoxin B1 and nitrosamines, which are metabolized to carcinogenic derivatives (Gonzalez and Gelboin, 1994; Honkakoski and Negishi, 1997; Pelkonen et al., 2000). Recently, Abu Bakar and colleagues characterized the CYP2A6 as human “Bilirubin Oxidizing Enzyme” and suggested that it plays an important role in cellular protection against oxidative stress by maintaining optimal levels of intracellular bilirubin: an endogenous, inducible antioxidant (Abu-Bakar et al., 2012, 2013). Regulation of the CYP2A6 gene expression is complex including both transcriptional and post-transcriptional processes. Several stress- and xenobiotic-activated transcription factors, such as the AhR, NRF2, PGC-1 and HnRNPA1 are known to regulate CYP2A6 at transcriptional level. In addition, the HnRNPA1 has been shown to up-regulate this gene also via mRNA


430 431 432

433

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8

470

stabilization. Our findings show that bilirubin regulates CYP2A6 via protein stabilization, due to its particularly high affinity to the active site (Abu-Bakar et al., 2013). Immobilization stress increased CYP2A1(Table 1) transcripts in the liver of young rats, but not in adults, suggesting that age plays a role in CYP2A1 regulation (Table 2) (Mikhailova et al., 2005). In addition, while restraint stress did not affect the constitutive, Cyp2a5-dependent coumarin hydroxylation in the murine liver, it strengthened the TCPOBOP-induced activity (Table 2) (Konstandi et al., 1998), indicating that the mechanism underlying the effect of stress on TCPOBOP-induced Cyp2a5 expression is distinct from that regulating the constitutive gene expression. It is possible therefore, that psychological stress can trigger signaling pathways that interfere with the induction of the Cyp2a5 by TCPOBOP- or other similar compounds, possibly leading to drug - stress interactions.

471

4.3. CYP2B

456 457 458 459 460 461 462 463 464 465 466 467 468 469

502

Several CYP2B isozymes have been identified in mammals, and CYP2B6 along with CYP2B7, are the major CYP2B isoforms detected in the human liver and lung, respectively (Table 1) (Czerwinski et al., 1994). They are involved in the metabolism of approximately 25% of the prescribed drugs, as well as of some pro-carcinogenic agents, such as aflatoxin B1 and dibenzanthracene (Lang et al., 2001; Martignoni et al., 2004; Xie and Evans, 2001). The nuclear receptor CAR is the main regulator of the CYP2B gene. Accordingly, ligands and activators of CAR (as well as many activators of PXR, due to cross reactivity of the two proteins) up-regulate the CYP2B genes. Such activators may include many clinically used drugs (Holloway et al., 2006; Pascussi et al., 2000; Plotsky, 1987). In contrast, some drugs, such as clonazepam, act as inhibitors of CYP2B isozymes (Bogaards et al., 2000). Repeated restraint stress significantly suppressed the constitutive CYP2B1/2-catalyzed pentoxyresorufin 7-depentylase activity (PROD) in the rat liver, whereas repeated mild unpredictable stress had no effect (Table 2). Restraint stress further enhanced CYP2B1/2 inducibility by B[␣]P, while mild unpredictable stress had only a minor effect (Table 2) (Czerwinski et al., 1994; Martignoni et al., 2006). These findings clearly show that the effect of stress on CYP2B inducibility by B[␣]P is stress-specific; restraint stress having a stronger impact than mild unpredictable stress. Furthermore, the mechanism underlying this effect of restraint stress seems different from that regulating the constitutive expression (Czerwinski et al., 1994; Martignoni et al., 2006). In light of the variability of CYP2B responses according to the stress type, the data suggest that individuals exposed to PAHs could experience greater induction of hepatic CYP2B expression when exposed to stress, and in turn, increased metabolism of drugs, CYP2B-substrates, with a subsequent increased risk of failed pharmacotherapy.

503

4.4. CYP2C

472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501

504 505 506 507 508 509 510 511 512 513 514 515 516 517

The CYP2C isoforms, CYP2C8, CYP2C9, CYP2C18 and CYP2C19 (Table 1), demonstrate a high amino acid sequence similarity (∼82%), and partially different substrate specificities (Zhou et al., 2009a). In general, the CYP2C enzymes are amongst the most important enzymes in the metabolism of clinically used drugs and are expressed in several organs besides the liver (Legraverend et al., 1992; Zhou et al., 2009b). Their substrates are numerous, including about 20% of all drugs in the market, such as pioglitazone, paclitaxel, statines, opioids, non-steroid anti-inflammatory drugs, phenytoin, warfarin, cyclophosphamide, tamoxifen and losartan (Legraverend et al., 1992; Martignoni et al., 2006; Zhou et al., 2009a,b). Many of these drugs are inducers of CYP2C enzymes by acting as ligands of CAR and PXR: the two principal transcription factors involved in the regulation of the encoding genes. Given the wide repertoire of

the CAR and PXR activator ligands, many of which are substrates of the CYP2C cytochromes, their up-regulation may lead to increased metabolism of not only the activators but other drugs as well, leading to drug–drug interactions at metabolic level and altered pharmacokinetics/pharmacodynamics during multidrug therapy (Legraverend et al., 1992; Zhou et al., 2009a,b). On the other hand, several drugs, such as amiodarone, omeprazole, losartane, fluconazole, sulfaphenazole and cimetidine act as inhibitors of CYP2C isozymes leading to decreased metabolism and elevated levels of drugs-substrates in plasma with potentially detrimental and even life-threatening consequences for the patients (Zhou et al., 2009a; Zuber et al., 2002). Recently, psychophysiological stress was shown to modify CYP2C expression in a stress-specific manner (Table 2). Early maternal deprivation stress (rat pups were deprived from their mothers for a 24 h period on postnatal day 9), up-regulated CYP2C11 expression in the liver of adult rats, whereas repeated restraint stress had no significant effect (Table 2). This study suggests that the stress-induced effect on CYP2C regulation should be attributed mainly to epinephrine, rather than glucocorticoids (Daskalopoulos et al., 2012a). It seems possible therefore, that stress and agents with adrenergic properties could interfere with CYP2C regulation in such a way, which could markedly increase the metabolism of CYP2C-substrates and lead to decreased efficacy of pharmacotherapy. 4.5. CYP2D Enzymes of the CYP2D subfamily (Table 1) constitute approximately the 4% of the total hepatic P450 content, but they are involved in the metabolism of over 30% of all prescribed drugs (Zuber et al., 2002). The CYP2D6 is the major isoform in humans, expressed in the liver, lung, kidney, small intestine, placenta, brain and breast to a variable extent (Niznik et al., 1990). Commercially available drugs metabolized by CYP2D6 include the majority of anti-psychotics and anti-depressants, along with several anti-arrythmics, beta-adrenoceptor and calcium channel blockers (Rendic and Guengerich, 2010). The CYP2D6 gene is considered non-inducible, but it is highly polymorphic leading to significant inter-individual variability in the expression and activity of the enzyme (Martignoni et al., 2006). In addition to the polymorphism, inhibition of the CYP2D6 during pharmacotherapy, can be of critical clinical importance, leading to accumulation of the drugs-substrates and potentially to toxic effects (Zanger et al., 2004). Detailed information about CYP2D substrates and inhibitors are provided by Rendic and Guengerich (2010) and Zanger et al. (2004). Although no direct hormonal regulation has been reported for CYP2D, psychological stress has been shown to modify hepatic CYP2D expression in a stress-specific manner. Exposure to repeated restraint stress up-regulated the hepatic expression of CYP2D1, whereas early maternal deprivation stress did not affect it (Table 2) (Daskalopoulos et al., 2012a). The up-regulating effect of restraint stress has been attributed to epinephrine, released from adrenal glands following stress (Daskalopoulos et al., 2012a). 4.6. CYP2E1 CYP2E1 (Table 1) accounts for approximately 6% of total P450 content in the human liver and catalyses the metabolism of 2% of the commercially available drugs (Zuber et al., 2002). Besides the liver, it is expressed in the lung, nasal epithelium and oropharynx and is regulated by several mechanisms including transcriptional and post-transcriptional processes (Novak and Woodcroft, 2000). Ethanol is an inducer and substrate of CYP2E1 (Salaspuro and Lieber, 1978). Acetaminophen, caffeine,


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chlorzoxazone and an array of carcinogens, such as benzene, styrene, acrylonitrile and nitrosamines are also metabolized by CYP2E1. Their metabolism often results in the production of reactive oxygen species (due to leakage of activated oxygen species from the enzyme substrate complex) causing liver injury and other detrimental effects (Legraverend et al., 1992; Wu and Cederbaum, 2003; Zhou et al., 2009b). Disulfiram and diethyldithiocarbamate are CYP2E1 inhibitors in humans (Ohashi et al., 2005). An experimental study using repeated restraint stress and mild unpredictable stress as experimental models of stress, showed that stress suppresses the hepatic CYP2E1-catalyzed p-nitrophenol hydroxylation (PNP) in rats (Table 2). The findings suggest that the effect of stress on constitutive CYP2E1 regulation is not stressspecific (Konstandi et al., 2000a; Matamoros and Levine, 1996). Theoretically, the reduced metabolism should lead to reduced toxicity of those toxicants requiring metabolic activation by CYP2E1. On the other hand, the biological effects of the elevated substrate concentrations are difficult to predict, and merit further investigations.

4.7. CYP3A The human CYP3A isoforms, CYP3A4, CYP3A5, CYP3A7 and CYP3A43 (Table 1), constitute almost 60% of the total P450 content in the liver (Spatzenegger and Jaeger, 1995). The vast majority of prescribed drugs are metabolized by the CYP3A isozymes (Liu et al., 2007) and several pro-drugs are converted to active molecules by the CYP3A4: the major CYP3A isoform in humans (Pelkonen and Raunio, 1997). In addition, CYP3A enzymes metabolize several pro-carcinogenic compounds to carcinogenic agents (Shimada and Guengerich, 1989). CYP3A isozymes also catalyze biosynthetic reactions of steroid hormones, cholesterol and lipids (Zhou et al., 2007). Many drugs, including rifampicin, dexamethasone, phenobarbital, carbamazepine and phenytoin induce CYP3A through activation of the nuclear receptors, CAR and PXR (Burk and Wojnowski, 2004; Liu et al., 2007), and several of them may also inhibit the CYP3As. Which of the two: induction or inhibition are more dominant, depends on the respective affinities of the drug to the enzyme and the regulatory factors (Zhou et al., 2007). Detailed information on CYP3A substrates, inducers and inhibitors are provided by Zhou et al. (2007) and Spatzenegger and Jaeger (1995). Early maternal deprivation stress leads to neurobiological changes in rats during adulthood that may have caused changes in their hepatic drug metabolizing profile; in particular, compared to controls, the constitutive CYP3A1/2 expression (Table 1) was up-regulated in the liver of adult rats, which had been maternally deprived early in their lives (Table 2). The up-regulation was mediated by the major effectors of the stress system, epinephrine and glucocorticoids. In contrast, exposure of adult rats to repeated restraint stress had no significant effect on CYP3A1 (Daskalopoulos et al., 2012a), although it increased Cyp3a expression in the murine liver (Table 2) (Daskalopoulos et al., 2012a). Jorgensen and colleagues reported no significant effect on CYP3A expression in the liver of Arctic charr following handling stress or exposure to high concentrations of corticosterone (Table 2) (Jorgensen et al., 2001). These studies suggest that while stress may have an impact on CYP3A regulation, it is stress-specific, which may be due to different neurochemical and neuroendocrine profiles observed in different types of stress (Konstandi et al., 2000b; Rentesi et al., 2013). It appears also that drugs with adrenergic properties or those that alter the glucocorticoid state may drastically up-regulate CYP3A, thus enhancing the CYP3A-catalyzed drug metabolism. Given the wide repertoire of drugs and carcinogens metabolized by the CYP3A isozymes, the up-regulation may result in failed pharmacotherapy or in increased production of toxic intermediates.

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4.8. CYP2J5 CYP2J5 is expressed in the kidney and to a lesser extend in the liver (Table 1). It is sexually dimorphic with higher levels of renal expression in males than in females (Ma et al., 1999, 2004). Renal CYP2J5 expression is regulated at pre-translational level by androgens and estrogens and is independent of growth hormone. Notably, androgens up-regulate CYP2J5, whereas estrogens have an opposite effect (Ma et al., 1999, 2004). Importantly, disruption of the Cyp2j5 gene causes spontaneous hypertension in mice. In particular, in female mice, CYP2J5 regulates blood pressure, proximal tubular fluid-electrolyte transport, and afferent arteriolar responsiveness via an estrogen-dependent mechanism (Athirakul et al., 2008). In both genders, the involvement of CYP2J5 in the regulation of blood pressure is attributed mainly to the renal CYP2J5-catalyzed transformation of arachidonic acid to cisepoxyeicosatrienoic acids (EET), which induce dilation of blood vessels and natriuresis (Athirakul et al., 2008; Flint et al., 2010; Ma et al., 2004). EET also affect the actions of several renal hormones, including renin, angiotensin II and arginine vasopressin (Roman, 2002; Zeldin, 2001). In addition to the above mentioned effects, CYP2J5 takes part in the synthesis of cholesterol, steroids and various lipids, as well as in the oxidation of testosterone, diclofenac and bufuralol (Ma et al., 1999, 2004). Flint et al. (2010) reported that 2 h of restraint stress increased Cyp2j5 expression in the livers of mice compared to non-stressed controls (Table 2). This finding further illuminates the mechanisms underlying the psychophysiological stress-induced modification of lipid and steroid homeostasis. 5. Stress-cytochrome P450 link: differential role of the primary stress response effectors The HPA axis and the central and peripheral components of the autonomous nervous system are the primary components of the stress response system and glucocorticoids are the final effectors resulting from activation of the HPA axis. Besides playing a role in the basal activity of the HPA axis and in the termination of the stress response, glucocorticoids control the homeostasis of multiple systems in the body (Johnson et al., 1992; Tsigos and Chrousos, 2002). Glucocorticoids exert their effects through cytoplasmic receptors that upon ligand binding translocate into the nucleus where they interact as homodimers with specific glucocorticoid responsive elements in the DNA to activate appropriate hormone-responsive genes. Activation of the sympathetic or parasympathetic components of the autonomic axes ensures a rapid response to control a wide range of functions, including cardiovascular, respiratory, gastrointestinal, renal, endocrine and neural functions. In addition to sympathetic innervation of peripheral organs from the efferent pre-ganglionic fibers, the sympathetic system also has a humoral contribution, which provides most of the circulating epinephrine and some of the norepinephrine from the adrenal medulla. In addition to these stress-specific systemic effects, stress may directly alter major drug-metabolizing enzymes in the liver, particularly the cytochrome P450s. These findings suggest differential roles of the two primary effectors of the stress response system, namely glucocorticoids and adrenergic pathways, on critical metabolic events. 5.1. Glucocorticoid regulation of cytochrome P450s The regulation of cytochromes is a complex process that involves multiple mechanisms including transcriptional regulation through ligand-activated nuclear receptors. The later serves as a critical step underlying hormone-controlled and xenobioticinduced expression of CYPs. To date, at least three distinct


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transcriptional mechanisms have been identified that participate in the glucocorticoid receptor (GR) -mediated control of CYP expression (Fig. 2): 1) direct binding of GR to a specific glucocorticoid responsive element on the gene-promoter; 2) indirect binding of a multiprotein complex, including GR, to gene promoters without a direct contact between GR and promoter DNA; and 3) transcriptional regulatory cross-talk between other CYP transcriptional regulators or nuclear receptors. Due to the variability of glucocorticoid effects on a wide-range of cellular pathways and functions, the final transcriptional impact of these steroid hormones on drug-metabolizing CYPs is believed to derive from a combination of diverse mechanisms (Dvorak and Pavek, 2010; Gross and Cidlowski, 2008). Despite the diversity of mechanisms potentially responsible for the transcriptional effects of glucocorticoids on drug metabolizing enzymes, however, a major role has been attributed to the effect of glucocorticoids on the synthesis and activity of an array of nuclear receptors that are critical regulators of CYP expression. Both, stress and the synthetic glucocorticoid, dexamethasone, have been reported to activate the transcription factors PXR, CAR, RXR␣ and HNF4␣ via the activation of GR (Khan et al., 2009). Interestingly, dexamethasone and another synthetic glucocorticoid, pregnenolone-16␣-carbonitrile (PCN), induce the synthesis of GR and PXR (El-Sankary et al., 2000; Khan et al., 2009; Pascussi et al., 2001). In vitro experiments using primary hepatocyte cultures treated with corticosterone and in vivo experiments using rats treated with dexamethasone, indicated a strong up-regulating effect of glucocorticoids on hepatic CYP3A1 and CYP3A2 expression at mRNA, apoprotein and CYP3A-dependent 6␤-testosterone hydroxylation levels (Table 2) (Daskalopoulos et al., 2012a). Dexamethasone also markedly increased the CYP3A-dependent erythromycin demethylation in freshly isolated peripheral blood lymphocytes (Dey et al., 2006), and glucocorticoids induced CYP3A5 expression in human pulmonary epithelial cells (Table 2) (Hukkanen et al., 2000). There are several studies demonstrating that the up-regulating effects of stress and glucocorticoids on CYP3A are associated with induction of the critical transcription factors mentioned above (Brtko and Dvorak, 2011; Daskalopoulos et al., 2012a; Dvorak et al., 2003; El-Sankary et al., 2002; Liddle et al., 1998; Pascussi et al., 2000, 2003, 2004; Pavek et al., 2007). Glucocorticoids are also inducers of CYP1A1/2 and CYP2B1 in the rat liver (Table 2) (Meredith et al., 2003). CYP2B isozymes are also inducible by glucocorticoids in the murine liver (Audet-Walsh et al., 2009). Glucocorticoids induce CYP2B6 and CYP2C8/9/19 in humans (Dvorak and Pavek, 2010; Pascussi et al., 2003) and CYP2C11 in rats (Table 2) (Daskalopoulos et al., 2012a). These effects are mediated directly by glucocorticoid binding to the GR and then to the GRE in the promoter of the CYP2C gene (Fig. 2) and indirectly, through the induction of CAR, PXR and RXR, which are known regulators of CYP2C (Brtko and Dvorak, 2011; Dvorak and Pavek, 2010). Glucocorticoid-related induction of CYP2C is a complex process. Glucocorticoids at low concentrations act as inducers of CYP2C (as in the case of CYP3A), whereas at high concentrations (e.g. in conditions inducing stress) they have an inhibiting effect (Bergeron et al., 1998; Iber et al., 1999). Finally, despite intense investigation, there are no reported effects of glucocorticoids or other hormones on CYP2D, with the exception of one finding that treatment of rat primary hepatocytes with corticosterone led to increased formation of CYP2D2 transcripts (Table 2) (Daskalopoulos et al., 2012a). 5.2. Adrenergic receptor-mediated regulation of cytochrome P450s Several studies have demonstrated the critical role of catecholamines in the regulation of cytochrome P450s (Fig. 1)

(Bromek et al., 2013; Konstandi et al., 1998, 2000a,b, 2004, 2005, 2006, 2013; Kot and Daniel, 2011). Although stress has been reported to be both up-, as well as down-regulating on CYP1A1 inducibility by B[␣]P, catecholamines play a fundamental role in both cases. Reserpine-induced depletion of central and peripheral catecholamines augmented the down-regulating effect of stress on CYP1A1 inducibility by B[␣]P. While guanethidineinduced peripheral catecholamine depletion markedly augmented the stress-mediated repression of CYP1A1 inducibility, peripheral epinephrine supplementation completely reversed this downregulating effect of stress. These later findings underscore the critical role of peripheral catecholamines in the stress-induced down-regulation of CYP1A1 inducibility by B[␣]P (Table 2) (Konstandi et al., 2004). It may be that peripheral catecholamines counteract with other stress-induced regulatory loops that negatively control CYP1A1 inducibility. Dexmedetomidine-induced NE inhibition in the hypothalamus was followed by a complete inhibition of the up-regulating effect of stress on CYP1A1 induction by B[␣]P, whereas stimulation of NE release in this brain site with atipamezole preserved the up-regulating effect of stress, indicating the critical role of central noradrenergic neurotransmission in this stress-induced up-regulating effect. Taken together the above findings indicate that the regulation of CYP1A1 induction by B[␣]P during stress involves both, central and peripheral catecholamines. The variability of outcomes potentially depends on the prevalence of the alterations in the function of various hormonal systems that are under noradrenergic control (Konstandi et al., 2004). Irrespective of stress, pharmacological manipulations of adrenergic receptor-linked pathways appear to play significant roles in the regulation of CYP1A1 in the rat liver. In particular, catecholamine depletion in the CNS and specifically, that of NE, as well as blockade of central ␣1 -ARs with prazosin, all were followed by up-regulation of constitutive CYP1A1. In contrast, isoprenaline-induced stimulation of beta-AR-linked pathways resulted in repression of constitutive CYP1A1 (Table 2) (Konstandi et al., 2005). The role of catecholamines in the stress-induced increase of CYP1A2 inducibility by B[␣]P is also well documented. In a state of a generalized catecholamine depletion induced by reserpine, the upregulating effect of stress on CYP1A2 inducibility was eliminated, which was also evident when only the peripheral catecholamines were depleted with guanethidine. These findings suggest a primary role of peripheral catecholamines, and a minor role of central catecholamines in CYP1A2 inducibility. The role of noradrenergicrelated pathways was evident as pharmacological manipulations of ␣2 -AR-linked pathways, using selective agonists and antagonists, markedly modified the stress-mediated increase in CYP1A2 induction by B[␣]P. In particular, stimulation of ␣2 -ARs with dexmedetomidine restricted the up-regulating effect of stress on CYP1A2 inducibility (Konstandi et al., 2008b). Independently of stress, drugs modifying central and peripheral catecholaminergic pathways appear to play critical roles in CYP1A2 regulation (Fig. 1). In particular, drug-induced catecholamine depletion in the CNS, inhibition of norepinephrine release (stimulation of ␣2 -ARs), and blockade of ␣1 -ARs, mainly in the CNS, all up-regulated CYP1A2 inducibility by B[␣]P at mRNA, apoprotein and methoxyresorufin 7-demethylase activity level (Table 2). On the other hand, peripheral ␣1 -ARs appear to mediate the phenylephrine-induced up-regulation of hepatic CYP1A2 (Table 2). Presumably, central noradrenergic systems counteract up-regulating factors, most likely via ␣1 - and ␣2 -ARs. Nonetheless, peripheral alpha- and beta-AR-linked pathways are potentially involved in the up-regulation of CYP1A2 induction by B[␣]P (Table 2) (Konstandi et al., 2006). In support of this hypothesis is the finding that B[␣]P binds directly to ␤2 -ARs in endothelial HMEC-1 cells, resulting in the


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Fig. 4. Signal transduction pathways related to adrenergic receptor-induced hepatic CYP up-regulation. Epinephrine and norepinephrine released from adrenal medulla following stress stimulate adrenergic receptors (AR) in hepatocytes. Although, both biogenic amines act as ligands of all types of ARs, epinephrine binds primarily to beta-ARs and norepinephrine to alpha-ARs (Waller et al., 2005). Stimulation of ␣1 and beta-ARs activates Gs-proteins, an event that is followed by activation of adenylyl cyclase (AC), which synthesizes cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Increased levels of cAMP result in elevated rates of protein kinase A (PKA) phosphorylation in the cytoplasm. Activated PKA phosphorylates the transcription factor CREB in the nucleus, which in turn forms dimmers with the CREB-binding protein (CBP) and the complex binds to a specific binding element on the promoter of the CYP target gene thus triggering the transcription. The opposite is true for the ␣2 -AR stimulation.

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activation of G protein/adenylyl cyclase/cAMP/Epac-1/IP3 pathway that stimulates [Ca2+ ] mobilization, which is essential for the B[␣]P-mediated induction of CYP1B1. Beta-blockers prevent this B[␣]P-induced effect. CYP1B1 is a prototypical AhR target gene belonging to the battery of AhR-regulated genes that also includes CYP1A1 and CYP1A2. Presumably, the ␤2 -AR-linked signaling pathway that is activated by PAHs is critical for the PAH-induced up-regulation of the AhR-dependent genes (Mayati et al., 2012). Taken together the above data indicate a potential transaction between the AhR-linked signaling pathways with those related to stress and ARs, that is critical in the regulation of CYP1A1/2 and CYP1B1 inducibility by B[␣]P (Konstandi et al., 2008b; Mayati et al., 2012). Epinephrine highly induces CYP3A1/2, CYP2C11 and CYP2D1/2 expression in rat liver (Table 2). Further investigation using primary hepatocyte cultures treated with ␣- and ␤-AR-agonists confirmed the significant role of hepatic AR-linked signaling pathways in the regulation of the above-mentioned CYPs. It appeared that direct stimulation of hepatic ␣1 - and ␤1/2 -ARs markedly induced CYP3A, CYP2C and CYP2D expression (Table 2) via activation of the c-AMP/PKA/CREB signaling pathway (Fig. 4). In the case of the ␤-AR-induced effect, the JNK-linked signaling pathway also participates (Fig. 4). The up-regulating effect of ␣2 -ARs on these CYPs is mainly mediated by the JNK-linked pathway. Drugs increasing intracellular cAMP induced the expression of Cyp2b10 (Table 2) and CAR in murine hepatocytes (Ding et al., 2006) and CYP3A1/2, CYP2C11 and CYP2D1/2 in rat hepatocytes (Daskalopoulos et al., 2012a). The in vivo administration of AR-agonists resulted in the down-regulation of CYP3A, CYP2C and CYP2D, despite the activation of the c-AMP/PKA/CREB signaling pathway in the liver of treated rats. Apparently, these drugs triggered in vivo the

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activation of other transcription factors, which restricted the transcriptional activity of CREB (Daskalopoulos et al., 2012a). Central noradrenergic innervation, and mainly that in the paraventicular and arcuate nucleus of the hypothalamus may also hold determinant roles in the negative regulation of CYP3A, CYP2C and CYP2D (Bromek et al., 2013). In the cascade of physiological changes observed following stimulation of ARs, alterations in blood pressure and liver hemodynamics affect the expression of several CYPs (Fig. 1) (Daskalopoulos et al., 2012a; Immink et al., 1978). In addition, ␣2 - and ␤2 -ARs, which are expressed on pancreatic ␤-cell membranes, control the release of insulin in response to increased plasma glucose levels (Fig. 3). In particular, stimulation of pancreatic ␣2 -ARs inhibits the release of insulin, whereas stimulation of ␤2 -ARs strengthens it; these effects are significant, because insulin displays a downregulating effect on various CYP genes (Woodcroft and Novak, 1997). The down-regulating effect of cytokines on CYP3A and CYP2C is also well documented and profoundly contributes to the AR-mediated down-regulating effect (Assenat et al., 2004; Carlson and Billings, 1996; Jover et al., 2002; Nadin et al., 1995; Vuppugalla et al., 2003). Epinephrine/norepinephrine, released following stress and AR-agonists, by stimulating ␣- and ␤-ARs expressed on the immune cell membranes, trigger the release of the cytokines, IL-1␤, IL-6 and TNF-␣ (Fig. 1) (Flierl et al., 2007, 2008, 2009), thus repressing the expression of the above mentioned CYPs (Daskalopoulos et al., 2012a). This effect may be mediated via binding of nitric oxide (NO) to the heme molecule, rendering the CYP/NO complex unstable (Carlson and Billings, 1996; Ebel et al., 1975). The bottom line is that the outcome of the in vivo stimulation of AR-systems, either following stress or treatment with AR-agonists on CYP3A, CYP2C and CYP2D, depends on the interplay between central and peripheral AR-linked pathways, which appear to override the direct up-regulating effect of the hepatic AR-related pathways on these CYPs (Daskalopoulos et al., 2012a). The stress- and AR-mediated alterations in CYP3A and CYP2C regulation is potentially mediated via cross-talk mechanisms involving the transcription factors CAR, PXR, RXR, HNF1␣, HNF4␣ and STAT5␤ (Daskalopoulos et al., 2012a; Jover et al., 2002; Leuenberger et al., 2009; Liddle et al., 1998; Wiwi and Waxman, 2004). In particular, exposure to early maternal deprivation stress induces the expression of PXR, an effect that is profoundly associated with the stress-induced up-regulation of CYP3A and CYP2C, whereas the AR-mediated repression of PXR and RXR expression is likely connected with the AR-induced down-regulation of these CYPs. In stress- and AR-mediated induction of CYP3A, HNF4␣ probably holds a key role by increasing the up-regulating effect of CAR and PXR on this cytochrome. On the other hand, the AR-induced suppression in the activation of the GH/STAT5␤ signaling pathway potentially contributes to the AR-induced down-regulation of the above mentioned CYPs, when AR-linked pathways are stimulated in vivo with AR-agonists. HNF4␣ and HNF1␣ profoundly participate in this regulatory pathway (Daskalopoulos et al., 2012a; Holloway et al., 2006; McMahon et al., 2001; Tsigos and Chrousos, 2002; Tuomisto and Mannisto, 1985; Wiwi and Waxman, 2004). Taken together these findings indicate the complex regulatory mechanisms involved in the stress- and AR-induced modifications in the regulation of the major CYP isozymes that catalyze the metabolism of the vast majority of prescribed drugs, toxicants and carcinogenic compounds. 6. Consequences of chronic stress While activation of the stress system results in behavioral and physical changes, which allow the organism to adapt, frequent, severe or chronic activation of the stress response system with


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the subsequent overexposure to stress hormones has been shown to disrupt many of the body’s physiologic processes. Ultimately, stress can affect many aspects of physiology and emotional status, and means of coping with stress can influence health and disease. With current trends in stress research that focus on understanding the mechanisms through which the stress-response is adaptive or becomes maladaptive, there is a growing association of stress system dysfunction, characterized by hyperactivity and/or hypoactivity to various pathophysiological states that cut across traditional boundaries of medical disciplines, including psychiatric, endocrine, inflammatory disorders and more recently, metabolic disorders. As described above, stress has a significant impact on some of the major drug-metabolizing enzyme systems. In turn, the expression of cytochrome P450s can be significantly altered in various disease states that have been typically associated with stress. Only a few of these stress-related diseases are outlined below to underscore the growing evidence showing their association with deregulation of the major drug metabolizing enzyme systems. Integrating studies from cellular and molecular pharmacology with biologically relevant physiologic systems as done in the studies present above, allows us to unravel the complex interplay between activation of the stress response system and disruption of normal drug metabolism in the liver. Stress is able to alter both, constitutive and induced cytochrome P450 expression, a property that renders stress a critical parameter in determining a drug’s pharmacokinetic profile. Below we critically examine the significance of recent findings regarding the consequences of stress in the regulation of the major drug metabolizing enzyme systems. An understanding of these relationships is a necessary prerequisite for predicting stress-drug interactions and developing improved drug dosing algorithms for effective and safe pharmacotherapy.

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6.1. Diseases and cytochrome P450s

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Increased vulnerability to various disease states have long been linked with chronic activation of the stress response system, and particularly with the HPA axis. Both, central and peripheral deregulation in HPA axis activity has been reported in chronic diseases including depression, type-2 diabetes mellitus, obesity, atherosclerosis-related diseases, and hypertension, among others (Arinc et al., 2005; Konstandi, 2013; Kotsovolou et al., 2010). There is accumulating evidence that these same diseases are associated with significantly altered hepatic drug metabolizing profiles. Although significant changes in drug metabolizing enzymes can be related to alterations in drug pharmacokinetics and pharmacodynamics, it remains to be resolved whether these changes are attributed to the disease process itself, or are related to deregulation of the stress response system and its peripheral effectors, which are typically present and characteristic of these diseases. 6.1.1. Type-2 diabetes and obesity Type-2 diabetes and obesity have a high prevalence across the world and both are associated with significantly increased morbidity and mortality rates. Hypercortisolemia from the chronic activation of the HPA axis and prolonged activation of the sympathetic nervous system during stress has been associated with the accumulation of visceral fat, which in turn, contributes to the clinical presentation of visceral obesity and type 2 diabetes (Kyrou and Tsigos, 2009). On the other hand, obesity constitutes a chronic stressful state that may also cause HPA axis dysfunction (Kyrou and Tsigos, 2007). In addition to changes in the stress response system, type 2 diabetes and obesity are associated with significant alterations in the hepatic expression of several drug-metabolizing enzymes, including CYP1A, CYP2B, CYP2E1, CYP3A, CYP4A, alpha-class GST, microsomal epoxide hydrolase and glutathione synthesis enzyme.

Recent studies elucidated an extensive crosstalk between PXR, CAR, RXR, AhR, C/EBP, HNF4␣, PPAR␣ and other nuclear receptors and transcription factors, linking xenobiotic metabolism to the homeostasis of lipids, bile acids, glucose and other endogenous processes, all of which are modified by stress and diseases for which stress is a significant component of their pathophysiological profile (Gao and Xie, 2012; Johnson et al., 1992; Moreau et al., 2008; Pelkonen et al., 2008; Tsigos and Chrousos, 2002; Yamaura et al., 2011). Nutrients and hormones regulate hepatic expression of several CYP isoforms in type-2 diabetes and obesity. The high levels of ketone bodies, a common feature in diabetes, are considered also responsible, at least in part, for the diabetes-mediated modification of CYP regulation (Bellward et al., 1988; Kim and Novak, 2007; Oh et al., 2012; Yun, 1992). It is well documented that insulin holds a prominent role in the diabetes-induced CYP regulation; insulin administration to chemically or spontaneously induced diabetic rats restores the expression of genes encoding drug-metabolizing enzymes to normal levels (Gonzalez and Gelboin, 1994; IngelmanSundberg, 2004a,b; Matamoros and Levine, 1996; Sheiner and Steimer, 2000; Waller et al., 2005). Notably, insulin has a downregulating effect on several hepatic CYPs including CYP2E1, CYP2B, CYP1A1, CYP1A2, CYP3A, CYP2C and CYP2D via the PI3K/AKT signaling pathway (Daskalopoulos et al., 2012a; Kim and Novak, 2007; Konstandi et al., 2008a; Oh et al., 2012). Based mainly on experimental data there is accumulating evidence suggesting that CYP regulation depends on the experimental models of diabetes and obesity applied. Ultimately, these effects are tissue-, isoform- and species-specific (Gandhi et al., 2012b). 6.1.2. Immune disorders Psychological stress has long been thought to be associated with the onset and exacerbations of autoimmune/inflammatory diseases with recent developments indicating that a relationship between stress-related disorders and autoimmunity may be rooted in a common neuroendocrine defect. Physical, psychological and inflammatory stressors, through stimulation of the CRH neuron, activate a final common neuroendocrine pathway, the HPA axis. This suggests that an association between stress and development of inflammatory disease may be related to alterations of this common pathway, or to defects in the intricate feedback loops that exist between the immune system and the central components of the nervous system (Johnson et al., 2006). Corticosteroids represent one of the most potent endogenous antiinflammatory agents known. They have the capacity to inhibit and suppress virtually all critical inflammatory and immune cell functions, even at physiological concentrations, and particularly, during the early development of the immune/inflammatory response. At the molecular level, they inhibit the production of most inflammatory mediators including IL-1, TNF␣, phospholipase A2 and prostaglandins. Hence, stress-induced enhanced production and secretion of glucocorticoids appears to counter-regulate and suppress excessive immune/inflammatory cell activation and mediator production that could otherwise result in self-induced tissue injury. This suggests a critical role for corticosteroids in maintaining physiological homeostasis during the adaptive response to noxious stressors (Chrousos, 2009; Chrousos and Kino, 2009; Johnson et al., 1992; Tsigos and Chrousos, 2002). In the cascade of events triggered by inflammation, activation of NF-kB can either directly down-regulate various CYPs through binding to NF-kB response elements in the promoter region of the corresponding CYP genes or can indirectly down-regulate CYPs through mutual repression of nuclear receptors and NF-kB (Abdulla et al., 2005; Assenat et al., 2004; Lee and Lee, 2005; Pascussi and Vilarem, 2008). Inflammation-mediated activation of mitogen activated protein kinase (MAPK) and c-Jun-N-terminal kinase (JNK), may also mediate the inflammation-induced changes in nuclear


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receptor and CYP regulation (Adam-Stitah et al., 1999; Ghose et al., 2004, 2008, 2009; Synold et al., 2001; Yu et al., 1999). Nitric oxide (NO) released from macrophages and hepatocytes during the inflammatory response, appears to play also a role in the regulation of various CYPs (Morris and Billiar, 1994). Alpha- and beta-ARs are expressed on various immune cells, such as macrophages, and play a role in regulating their inflammatory potential. Upon exposure to stress, epinephrine and norepinephrine released from the adrenal medulla stimulate both alpha- and beta-ARs and trigger the secretion of IL-1␤, IL-6 and TNF␣ (Flierl et al., 2007, 2008, 2009). In vivo and in vitro experiments have shown that these cytokines down-regulate hepatic CYP3A and CYP2C expression (Assenat et al., 2004; Carlson and Billings, 1996; Jover et al., 2002; Nadin et al., 1995; Vuppugalla et al., 2003), potentially via NO, which binds to the heme molecule, thus rendering the NO/CYP complex unstable (Carlson and Billings, 1996; Ebel et al., 1975). Of the various cytokines, TNF␣ has the most potent down-regulating effect on CYPs, predominately on the CYP3A isozymes (Gandhi et al., 2012b; Kinloch et al., 2011; Warren et al., 1999, 2001). 6.1.3. Cancer Stress-induced immune deregulation results in significant health consequences related to immune disorders including the onset and progression of various cancers (Balkwill and Mantovani, 2001; Chrousos and Gold, 1992; Johnson et al., 1992). There is growing evidence that stress and the resulting changes in behavior, immune status and stress hormone profiles (particularly catecholamines), significantly influence tumor initiation, progression and metastasis (Powell et al., 2013). In addition to the above mentioned stress-induced neurobiological alterations that affect cancer initiation and propagation, the finding of decreased hepatic microsomal drug metabolizing activity in tumor bearing rats is clinically significant (Kato et al., 1963). This is because several anticancer drugs, such as cyclophosphamide, are pro-drugs that are metabolized to the active drug in the tumors (Chen et al., 2004). Notably, there are also reports on increased CYP expression in tumors, suggesting that this complex issue needs further investigation. In particular, it has been reported that CYP2A5 is upregulated in hepatic preneoplastic cells, an initial phase of tumor growth (Wastl et al., 1998) and in hepatocellular carcinomas (Kobliakov et al., 1993). As Cyp2a5 and CYP2A6 appear to have a dual function, a cytoprotective and a cytotoxic, the clinical consequences of CYP2A induction depend on the type of chemicals the individual is simultaneously exposed to. In case of cigarette smokers that are also exposed to stress there is increased risk to develop cancer related to pro-carcinogens found in the cigarette smoke and tar that are metabolized to carcinogenic products by CYP1A1/2, CYP1B1 and CYP2A5/CYP2A6 (Kobayashi et al., 2003; Kobliakov et al., 1993; Newton et al., 1995; Pelkonen et al., 2000; Shimada et al., 1998; Xu et al., 2005). Cancer-induced changes in the synthesis and activation of drug metabolizing enzymes and transporters is potentially regulated by the over-expression of NF-kB. The downregulation of PXR and CAR that is observed in tumor-bearing mice also actively participates in the tumor-mediated regulation of various CYPs (Kacevska et al., 2011). These findings taken together with the fact that most anticancer drugs have a very low or narrow therapeutic index, suggest that stress-, glucocorticoid- or AR-induced modifications in the drug metabolizing enzyme activity can result in life-threatening adverse drug reactions or even in failure of chemotherapy (Gandhi et al., 2012a). 6.1.4. Cardiovascular diseases-metabolic syndrome Stress is considered as a fundamental causative factor of several cardiovascular disorders (Chrousos, 2009; Chrousos and Gold, 1992; Chrousos and Kino, 2009; Johnson et al., 1992). In particular,

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psychosocial stress appears to contribute to increased vulnerability for acute coronary syndrome onset, which by more recent multifactorial approaches reflects a confluence of events and processes, such as atherosclerotic plaque formation, coronary flow dynamics, hemostatic function, metabolic and inflammatory conditions, neuroendocrine deregulation, as well as environment (Burg et al., 2013). Given the fact that in humans, cytochrome P450s are responsible for the metabolism of a large number of drugs used in the treatment of cardiovascular disorders, such as beta-blockers, calcium channel blockers and angiotensin II receptor antagonists (Abernethy and Flockhart, 2000), the effect of stress and related diseases on CYP regulation is of paramount significance. Alterations in drug metabolizing enzymes could be of particular clinical relevance in patients especially, with heart failure and hypertension. Notably, heart failure is associated with an increase in CYP2J2, CYP1B1, CYP2E1, CYP4A10 and CYP2F2 gene expression (Satoh et al., 2002; Tan et al., 2002). It should be also noted that genetic polymorphisms of various CYPs are commonly associated with heart failure and hypertension (Kivisto et al., 2005). In the cascade of events induced by stress in the hearts of patients with congestive heart failure is the increased production of reactive oxygen species and release of proinflammatory cytokines that may be responsible for the alterations in the activation of various CYPs including CYP2C19 and CYP1A2 (Fliser et al., 2004; Frye and Branch, 2002). A recent report showed that coronary artery disease was associated with a genotype of CYP8A1 (Bousoula et al., 2012). Of clinical interest is also the fact that specific cytochromes (e.g., CYP2B, CYP2C8, CYP2C9, CYP2C10 and CYP2J2) that are expressed in the human vascular smooth muscle and endothelium, participate in the regulation of vascular tone and homeostasis, and thus, play a role in moderating blood pressure, while, uncontrolled hypertension favors the up-regulation of various CYPs (Carlson and Billings, 1996). Among the complications of a chronically activated stress response is metabolic syndrome, which has been described as a state of deranged metabolic homeostasis (Kyrou et al., 2006). Metabolic syndrome is basically a maturity-onset disease that is related to an immune response, countered by a permanent increase in glucocorticoids (Alemany, 2012). High levels of glucocorticoids keep the immune system at bay, but induce insulin resistance, alter lipid metabolism, favor fat deposition, lipotoxicity, mobilize protein and decrease androgen synthesis, among others. Metabolic syndrome has been connected with increased incidence of atherosclerosis, myocardial infarct, congestive heart failure and carcinogenesis. Indications exist that alterations in CYP activation may participate in the pathogenesis of metabolic syndrome (Murray, 2006). Experimental studies using animal models of obesity or diabetes, and feeding protocols based on hyperlipidemic diets, indicated that in these states of deregulated lipid and carbohydrate homeostasis, several CYPs were up-regulated including CYP2E1 and CYP1A2. In the liver of rodents following a diet supplemented with corn oil, a weak up-regulation was observed in basal CYP2B apoprotein levels, pentoxyresorufin O-depentylation, CYP4A fatty acid hydroxylation, CYP3A-dependent testosterone 6␤-hydroxylation and erythromycin N-demethylation (Gonzalez et al., 1991; Kraner et al., 1993; Raucy et al., 1991; Yoo et al., 1990, 1992; Yun, 1992). In contrast, a choline deficient diet for 10 weeks resulted in a down-regulation of the GH-responsive cytochromes, CYP2C11 and CYP3A2, in rodents (Murray et al., 1987, 1992). This type of diet though, increased CYP2B and CYP2E1 inducibility by phenobarbital (Konstandi et al., 2009). 6.1.5. Depression A critical factor in the pathophysiology of depression stems from abnormality in the counter-regulation of the stress response, which


1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181

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G Model NBR 1957 1–19 14 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217


results in CRH and central noradrenergic hypersecretion (Johnson et al., 1992). In particular, abnormalities or defects in the positive regulation and counter-regulation, respectively, of the main components of the adrenocortical and adrenergic systems in individuals exposed to chronic uncontrolled stress, are considered as responsible in the pathogenesis of depression (de Kloet et al., 2005; Gold et al., 1988; McEwen, 2000). This disease state has been associated with alterations in the hormonal status and nutritional profile of the patients (Chrousos and Gold, 1992; Tsigos and Chrousos, 2002). An experimental study using the Flinders Sensitive Line (FSL) of rats, an animal model of depression (Overstreet, 2012; Overstreet et al., 2005), showed that several key enzymes of the hepatic biotransformation machinery are differently expressed in FSL rats compared to Sprague Dawley controls. In particular, glutathione (GSH) content, GST activity and the expression of several CYPs, including CYP2B1, CYP2C11 and CYP2D1 are lower in FSL rats compared to controls (Kotsovolou et al., 2010). In contrast, p-nitrophenol hydroxylase, 7-ethoxyresorufin-O-dealkylase and 16␣-testosterone hydroxylase activities are detected at higher levels in FSL rats. Importantly, PAHs induce CYP1A1, CYP1A2 and CYP2B1/2 expression to a lesser extent in FSL than in control rats. Of clinical interest is the fact that the antidepressant mirtazapine that acts mainly via inhibition of central ␣2 -adrenergic and serotonergic systems (Schule et al., 2004) up-regulates several CYPs in the liver of FSL rats that metabolize the majority of commercially available drugs, including CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2 (Kotsovolou et al., 2010). These findings indicate that the neurobiological alterations observed in depression may lead to a modified hepatic drug metabolizing capacity, a condition that may influence the outcome of drug therapy. The critical role of antidepressant treatment should be always taken into account when designing a therapeutic scheme and in the interpretation of insufficient pharmacotherapy or side effects.

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6.1.6. Stress-related choices in life-style Stress has long been associated with a range of life-style impulses, including increased drinking, cigarette smoking, fasting or over-eating (Hamilton et al., 2013; Karasu, 2012; Margolis, 2013). The altered nutritional status and hormonal profile observed in fasting and/or over-eating, long-term alcohol consumption and cigarette smoking (conditions frequently associated with stress) have been connected with the up-regulation of hepatic CYP2E1, CYP1A and other CYPs (Gandhi et al., 2012a). In particular, cigarette smoking could drastically increase the hepatic metabolism of various pro-carcinogens belonging to PAHs via induction of CYP1A isozymes (Lang et al., 1994; Nebert et al., 1991b; Pasanen and Pelkonen, 1994). Alcohol consumption has been connected with alterations in drug pharmacokinetics by altering gastric emptying or hepatic drug metabolism by inducing mainly CYP2E1 (Fraser, 1997; Kim and Novak, 2007). During fasting, the expression of hepatic drug metabolizing enzymes of phase I and II may be markedly altered, thus modifying the metabolism of xenobiotics, pro-carcinogens, carcinogens, toxicants and therapeutic agents (Kim and Novak, 2007). These vital alterations in life style, may lead to complications in drug therapy, increased drug toxicity and carcinogenicity, mainly due to the increased production of reactive oxygen species and carcinogenic products (Gonzalez and Gelboin, 1994; Gonzalez and Yu, 2006; Konstandi et al., 2000a, 2006, 2007, 2008b; Lang et al., 1994; Nebert et al., 1991b; Nebert and Russell, 2002; Pasanen and Pelkonen, 1994).

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6.2. Drug pharmacokinetics and stress

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The pharmacological term “pharmacokinetics” describes the dynamics of the fundamental processes, absorption, distribution,

metabolism and elimination, which determine the fate of a particular drug in the body (Konstandi, 2013; Waller et al., 2005). Several factors including psychophysiological stress can modify these pharmacokinetic parameters (Konstandi, 2013; Peng and Cheung, 2011). Exposure of soldiers to major physical stressors, such as acute or chronic exercise or extreme physical activity, is followed by a decreased blood flow to visceral organs, a phenomenon that results in reduced drug absorption by the gastrointestinal track (Peng and Cheung, 2011). Hepatic drug metabolism and renal elimination was also decreased in these soldiers. On the other hand, exercise increased blood flow in the working muscles, followed by increased absorption of a drug when was intramuscularly administered. The alterations in several physiological parameters occurred during stress, such as increased plasma cortisol and low density lipoprotein levels, increased blood pressure and sweating, and changes in cardiovascular, respiratory and gastrointestinal functions are considered responsible for the modification of the drug’s pharmacokinetic profile following stress (Flaten et al., 1999; Peng and Cheung, 2011). In summary, a drug’s action is largely dependent on metabolism. Virtually all pharmaceutical substances entering the body are subjected to critical biotransformation in the liver, which usually leads to inactivation of the parent compound or to its conversion to active metabolic products; this process is primarily catalyzed by cytochrome P450s (Cribb et al., 2005; Gonzalez, 2005; Gonzalez and Gelboin, 1994; Gonzalez and Yu, 2006; Guengerich, 2003; Ingelman-Sundberg, 2004b; Xu et al., 2005). Stress in various forms is able to modify the activity of the major drug-metabolizing cytochromes. Following stress various events appear to hold determinant roles in CYP regulation. These include, activation of the HPA axis with the consequent release of glucocorticoids and epinephrine from adrenal glands, oxidative stress, increased release of cytokines/NF-kB and the altered secretion of hormones, such as GH, thyroid hormones and insulin (Dvorak and Pavek, 2010; Kennedy and Riji, 1998; Zordoky and El-Kadi, 2009). Stress functions as a potent modifying factor with unique properties, and not in a drug-like fashion with dose- and time-dependent specificities. For the most part, stress up-regulates constitutive CYP expression, with the exception of CYP2E1 and CYP2B, which are down-regulated by stress. CYP1A, CYP2A, CYP2C, CYP3A and CYP2D metabolize the majority of commercially available drugs; stress-induced up-regulation of these enzymes could result in increased metabolism of their drugs-substrates and consequent reduction of drug efficacy. In contrast, down-regulation of CYP2E1 and CYP2B by stress would presumably lead to reduced metabolism of their drugs-substrates resulting in their increased plasma levels and potential toxic effects (Arinc et al., 2005; Czerwinski et al., 1994; Gonzalez, 2005; Konstandi et al., 2008a; Lang et al., 2001; Nebert et al., 1991a). It should be noted though that the stress-induced up-regulation of CYPs that catalyze the metabolism of pro-drugs, will result in increased drug-activation, whereas reduced pro-drug activation will happen in the case of CYP down-regulation (Konstandi, 2013). Therefore, stress should be considered as a dynamic factor and critical player in the regulation of the major drug metabolizing CYP isozymes. As both the adrenergic receptor-linked pathways and glucocorticoids play primary, albeit differential roles in the stress-induced regulation of CYPs, agents acting as adrenergic receptor agonists or antagonists or those that can alter the status of glucocorticoids may also modify drug metabolism and consequently, drug pharmacokinetics and pharmacodynamics. Clinically, both in terms of pharmacotherapy and drug toxicity, the stress- and adrenergic receptor-mediated interactions with drugs, underscore the necessity to carefully reconsider drug dosing regimes, in order to ensure the optimal action of the drugs and minimize their side effects (Konstandi, 2013).


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7. Conclusion Stress has an important impact on hepatic drug metabolism. This is due to its role in the regulation of the major drug metabolizing enzyme systems, mainly those belonging to Phase I. The effects of stress are enzyme-, species- and stress-specific. Stress is able to alter both constitutive and induced cytochrome P450 expression. This property renders stress a critical parameter in determining a drug’s pharmacokinetic profile and subsequently, affects pharmacotherapy and toxicity outcomes. The major effectors of the stress response, the adrenergic receptor-linked pathways and glucocorticoids, appear to play primary and distinct roles in the stress-mediated regulation of CYPs. Although the main body of available data come from experimental animal models, and the findings can not be directly extrapolated to the human condition, they support the notion that the patient’s stress profile potentially should be considered when designing a therapeutic scheme, in particular when it is based on multiple drugs of vital importance to the patient, or on drugs with small therapeutic windows or with significant side-effects. Therefore, for optimizing the therapeutic efficacy of prescribed drugs and minimizing their adverse reactions, the elimination or consideration of stress is a perquisite. The findings outlined in this review are aimed at providing a basis for stimulating further investigation on physiologically-relevant pharmacokinetic and pharmacodynamic models within a clinical framework. By understanding the complex, multi-faceted and multi-level interplay between drug and organism, the aim would be to ultimately implement and translate pharmacogenetic testing in personalized medicine (Eissing et al., 2011; Holzhutter et al., 2012; RostamiHodjegan and Tucker, 2007; Zanger and Schwab, 2013). References Abdulla, D., Goralski, K.B., Del Busto Cano, E.G., Renton, K.W., 2005. The signal transduction pathways involved in hepatic cytochrome P450 regulation in the rat during a lipopolysaccharide-induced model of central nervous system inflammation. Drug Metab. Dispos. 33, 1521–1531. Abernethy, D.R., Flockhart, D.A., 2000. Molecular basis of cardiovascular drug metabolism: implications for predicting clinically important drug interactions. Circulation 101, 1749–1753. Abu-Bakar, A., Arthur, D.M., Wikman, A.S., Rahnasto, M., Juvonen, R.O., Vepsalainen, J., Raunio, H., Ng, J.C., Lang, M.A., 2012. Metabolism of bilirubin by human cytochrome P450 2A6. Toxicol. Appl. Pharmacol. 261, 50–58. Abu-Bakar, A., Hakkola, J., Juvonen, R., Rahnasto-Rilla, M., Raunio, H., Lang, M.A., 2013. Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults in the liver. Curr. Drug Metab. 14, 137–150. Adam-Stitah, S., Penna, L., Chambon, P., Rochette-Egly, C., 1999. Hyperphosphorylation of the retinoid X receptor alpha by activated c-Jun NH2-terminal kinases. J. Biol. Chem. 274, 18932–18941. Aguilera, G., Abou Samra, A.B., Harwood, J.P., Catt, K.J., 1988. Corticotropin releasing factor receptors: characterization and actions in the anterior pituitary gland. Adv. Exp. Med. Biol. 245, 83–105. Alemany, M., 2012. Do the interactions between glucocorticoids and sex hormones regulate the development of the metabolic syndrome? Front. Endocrinol. (Lausanne) 3, 27. Anguizola, J.A., Basiaga, S.B., Hage, D.S., 2013. Effects of fatty acids and glycation on drug interactions with human serum albumin. Curr. Metabolomics 1, 239–250. Arinc, E., Arslan, S., Adali, O., 2005. Differential effects of diabetes on CYP2E1 and CYP2B4 proteins and associated drug metabolizing enzyme activities in rabbit liver. Arch. Toxicol. 79, 427–433. Assenat, E., Gerbal-Chaloin, S., Larrey, D., Saric, J., Fabre, J.M., Maurel, P., Vilarem, M.J., Pascussi, J.M., 2004. Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Hepatology 40, 951–960. Athirakul, K., Bradbury, J.A., Graves, J.P., DeGraff, L.M., Ma, J., Zhao, Y., Couse, J.F., Quigley, R., Harder, D.R., Zhao, X., Imig, J.D., Pedersen, T.L., Newman, J.W., Hammock, B.D., Conley, A.J., Korach, K.S., Coffman, T.M., Zeldin, D.C., 2008. Increased blood pressure in mice lacking cytochrome P450 2J5. FASEB J. 22, 4096–4108. Audet-Walsh, E., Auclair-Vincent, S., Anderson, A., 2009. Glucocorticoids and phenobarbital induce murine CYP2B genes by independent mechanisms. Expert Opin. Drug Metab. Toxicol. 5, 1501–1511. Balkwill, F., Mantovani, A., 2001. Inflammation and cancer: back to Virchow? Lancet 357, 539–545. Barclay, T.B., Peters, J.M., Sewer, M.B., Ferrari, L., Gonzalez, F.J., Morgan, E.T., 1999. Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific and peroxisome proliferator-activated receptor-alpha dependent. J. Pharmacol. Exp. Ther. 290, 1250–1257.

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Bellward, G.D., Chang, T., Rodrigues, B., Mcneill, J.H., Maines, S., Ryan, D.E., Levin, W., Thomas, P.E., 1988. Hepatic cytochrome-P-450j induction in the spontaneously diabetic Bb rat. Mol. Pharmacol. 33, 140–143. Bergeron, R.M., Serron, S.C., Rinehart, J.J., Cawley, G.F., Backes, W.L., 1998. Pituitary component of the aromatic hydrocarbon-mediated expression of CYP2B and CYP2C11. Xenobiotica 28, 303–312. Bernardini, R., Kamilaris, T.C., Calogero, A.E., Johnson, E.O., Gomez, M.T., Gold, P.W., Chrousos, G.P., 1990. Interactions between tumor necrosis factor-alpha, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat. Endocrinology 126, 2876–2881. Bird, S.J., Kuhar, M.J., 1977. Iontophoretic application of opiates to the locus coeruleus. Brain Res. 122, 523–533. Bogaards, J.J., Bertrand, M., Jackson, P., Oudshoorn, M.J., Weaver, R.J., van Bladeren, P.J., Walther, B., 2000. Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica 30, 1131–1152. Boissy, A., 1995. Fear and fearfulness in animals. Q. Rev. Biol. 70, 165–191. Bousoula, E., Kolovou, V., Vasiliadis, I., Karakosta, A., Xanthos, T., Johnson, E.O., Skandalakis, P., Kolovou, G.D., 2012. CYP8A1 gene polymorphisms and left main coronary artery disease. Angiology 63, 461–465. Bromek, E., Wojcikowski, J., Daniel, W.A., 2013. Involvement of the paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus in the central noradrenergic regulation of liver cytochrome P450. Biochem. Pharmacol. 86, 1614–1620. Brtko, J., Dvorak, Z., 2011. Role of retinoids, rexinoids and thyroid hormone in the expression of cytochrome P450 enzymes. Curr. Drug Metab. 12, 71–88. Burg, M.M., Edmondson, D., Shimbo, D., Shaffer, J., Kronish, I.M., Whang, W., Alcantara, C., Schwartz, J.E., Muntner, P., Davidson, K.W., 2013. The ‘perfect storm’ and acute coronary syndrome onset: do psychosocial factors play a role? Prog. Cardiovasc. Dis. 55, 601–610. Burk, O., Wojnowski, L., 2004. Cytochrome P450 3A and their regulation. Naunyn. Schmiedebergs Arch. Pharmacol. 369, 105–124. Carlson, T.J., Billings, R.E., 1996. Role of nitric oxide in the cytokine-mediated regulation of cytochrome P-450. Mol. Pharmacol. 49, 796–801. Charmandari, E., Kino, T., Souvatzoglou, E., Chrousos, G.P., 2003. Pediatric stress: hormonal mediators and human development. Horm. Res. 59, 161–179. Chen, C.-S., Lin, J.T., Goss, K.A., He, Y.-a., Halpert, J.R., Waxman, D.J., 2004. Activation of the anticancer prodrugs cyclophosphamide and ifosfamide: identification of cytochrome P450 2B enzymes and site-specific mutants with improved enzyme kinetics. Mol. Pharmacol. 65, 1278–1285. Cheng, P.Y., Morgan, E.T., 2001. Hepatic cytochrome P450 regulation in disease states. Curr. Drug Metab. 2, 165–183. Chida, Y., Sudo, N., Kubo, C., 2006. Does stress exacerbate liver diseases? J. Gastroenterol. Hepatol. 21, 202–208. Chida, Y., Sudo, N., Sonoda, J., Hiramoto, T., Kubo, C., 2007. Early-life psychological stress exacerbates adult mouse asthma via the hypothalamus–pituitary–adrenal axis. Am. J. Respir. Crit. Care Med. 175, 316–322. Choudhary, D., Jansson, I., Stoilov, I., Sarfarazi, M., Schenkman, J.B., 2005. Expression patterns of mouse and human CYP orthologs (families 1–4) during development and in different adult tissues. Arch. Biochem. Biophys. 436, 50–61. Chrousos, G.P., 2009. Stress and disorders of the stress system. Nat. Rev. Endocrinol. 5, 374–381. Chrousos, G.P., Gold, P.W., 1992. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 1244–1252. Chrousos, G.P., Kino, T., 2009. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. Ann. N. Y. Acad. Sci. 1179, 153–166. Cribb, A.E., Peyrou, M., Muruganandan, S., Schneider, L., 2005. The endoplasmic reticulum in xenobiotic toxicity. Drug Metab. Rev. 37, 405–442. Cure, M., Rolinat, J.P., 1992. Behavioral heterogeneity in Sprague–Dawley rats. Physiol. Behav. 51, 771–774. Czerwinski, M., McLemore, T.L., Gelboin, H.V., Gonzalez, F.J., 1994. Quantification of CYP2B7, CYP4B1, and CYPOR messenger RNAs in normal human lung and lung tumors. Cancer Res. 54, 1085–1091. Danielson, P.B., 2002. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr. Drug Metab. 3, 561–597. Daskalopoulos, E.P., Lang, M.A., Marselos, M., Malliou, F., Konstandi, M., 2012a. D(2)dopaminergic receptor-linked pathways: critical regulators of CYP3A, CYP2C, and CYP2D. Mol. Pharmacol. 82, 668–678. Daskalopoulos, E.P., Malliou, F., Rentesi, G., Marselos, M., Lang, M.A., Konstandi, M., 2012b. Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: role of adrenergic receptor signaling pathways. Am. J. Physiol. Endocrinol. Metab. 303, 40–54. de Kloet, E.R., Joels, M., Holsboer, F., 2005. Stress and the brain: from adaptation to disease. Nat. Rev. Neurosci. 6, 463–475. Dey, A., Yadav, S., Dhawan, A., Seth, P.K., Parmar, D., 2006. Evidence for cytochrome P450 3A expression and catalytic activity in rat blood lymphocytes. Life Sci. 79, 1729–1735. Ding, X., Lichti, K., Kim, I., Gonzalez, F.J., Staudinger, J.L., 2006. Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. J. Biol. Chem. 281, 26540–26551. Dipple, A., 1983. Formation, metabolism, and mechanism of action of polycyclic aromatic hydrocarbons. Cancer Res. 43, 2422s–2425s. du Souich, P., Fradette, C., 2011. The effect and clinical consequences of hypoxia on cytochrome P450, membrane carrier proteins activity and expression. Expert Opin. Drug Metab. Toxicol. 7, 1083–1100.


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Dvorak, Z., Modriansky, M., Pichard-Garcia, L., Balaguer, P., Vilarem, M.J., Ulrichova, J., Maurel, P., Pascussi, J.M., 2003. Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9, and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation. Mol. Pharmacol. 64, 160–169. Dvorak, Z., Pavek, P., 2010. Regulation of drug-metabolizing cytochrome P450 enzymes by glucocorticoids. Drug Metab. Rev. 42, 621–635. Ebel, R.E., O’Keefe, D.H., Peterson, J.A., 1975. Nitric oxide complexes of cytochrome P-450. FEBS Lett. 55, 198–201. Eissing, T., Kuepfer, L., Becker, C., Block, M., Coboeken, K., Gaub, T., Goerlitz, L., Jaeger, J., Loosen, R., Ludewig, B., Meyer, M., Niederalt, C., Sevestre, M., Siegmund, H.U., Solodenko, J., Thelen, K., Telle, U., Weiss, W., Wendl, T., Willmann, S., Lippert, J., 2011. A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front. Physiol. 2, 4. El-Sankary, W., Bombail, V., Gibson, G.G., Plant, N., 2002. Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein:DNA interaction distinct from the pregnane X receptor response element. Drug Metab. Dispos. 30, 1029–1034. El-Sankary, W., Plant, N.J., Gibson, G.G., Moore, D.J., 2000. Regulation of the CYP3A4 gene by hydrocortisone and xenobiotics: role of the glucocorticoid and pregnane X receptors. Drug Metab. Dispos. 28, 493–496. Ellenbroek, B.A., van den Kroonenberg, P.T., Cools, A.R., 1998. The effects of an early stressful life event on sensorimotor gating in adult rats. Schizophr. Res. 30, 251–260. Exton, J.H., 1985. Mechanisms involved in alpha-adrenergic phenomena. Am. J. Physiol. 248, E633–E647. File, S.E., Clarke, A., 1981. Exploration and motor activity after intraventricular ACTH, morphine and naloxone. Behav. Brain Res. 2, 223–227. Flaten, M.A., Simonsen, T., Olsen, H., 1999. Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosom. Med. 61, 250–255. Flierl, M.A., Rittirsch, D., Huber-Lang, M., Sarma, J.V., Ward, P.A., 2008. weapons in the inflammatory arsenal of Catecholamines-crafty immune/inflammatory cells or opening pandora’s box? Mol. Med. 14, 195–204. Flierl, M.A., Rittirsch, D., Nadeau, B.A., Chen, A.J., Sarma, J.V., Zetoune, F.S., McGuire, S.R., List, R.P., Day, D.E., Hoesel, L.M., Gao, H., Van Rooijen, N., Huber-Lang, M.S., Neubig, R.R., Ward, P.A., 2007. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449, 721–725. Flierl, M.A., Rittirsch, D., Nadeau, B.A., Sarma, J.V., Day, D.E., Lentsch, A.B., HuberLang, M.S., Ward, P.A., 2009. Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response. PLoS One 4, e4414. Flint, M.S., Hood, B.L., Sun, M., Stewart, N.A., Jones-Laughner, J., Conrads, T.P., 2010. Proteomic analysis of the murine liver in response to a combined exposure to psychological stress and 7,12-dimethylbenz(a)anthracene. J. Proteome Res. 9, 509–520. Fliser, D., Buchholz, K., Haller, H., 2004. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation 110, 1103–1107. Fraser, A.G., 1997. Pharmacokinetic interactions between alcohol and other drugs. Clin. Pharmacokinet. 33, 79–90. Frye, R.F., Branch, R.A., 2002. Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects. Br. J. Clin. Pharmacol. 53, 155–162. Gandhi, A., Moorthy, B., Ghose, R., 2012a. Drug disposition in pathophysiological conditions. Curr. Drug Metab. 13, 1327–1344. Gandhi, A.S., Guo, T., Shah, P., Moorthy, B., Chow, D.S., Hu, M., Ghose, R., 2012b. CYP3A-dependent drug metabolism is reduced in bacterial inflammation in mice. Br. J. Pharmacol. 166, 2176–2187. Gao, J., Xie, W., 2012. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol. Sci. 33, 552–558. Ghose, R., Guo, T., Haque, N., 2009. Regulation of gene expression of hepatic drug metabolizing enzymes and transporters by the Toll-like receptor 2 ligand, lipoteichoic acid. Arch. Biochem. Biophys. 481, 123–130. Ghose, R., White, D., Guo, T., Vallejo, J., Karpen, S.J., 2008. Regulation of hepatic drugmetabolizing enzyme genes by toll-like receptor 4 signaling is independent of toll-interleukin 1 receptor domain-containing adaptor protein. Drug Metab. Dispos. 36, 95–101. Ghose, R., Zimmerman, T.L., Thevananther, S., Karpen, S.J., 2004. Endotoxin leads to rapid subcellular re-localization of hepatic RXRalpha: a novel mechanism for reduced hepatic gene expression in inflammation. Nucl. Recept. 2, 4. Gold, P.W., Goodwin, F.K., Chrousos, G.P., 1988. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (1). N. Engl. J. Med. 319, 348–353. Gonzalez, F.J., 1988. The molecular biology of cytochrome P450s. Pharmacol. Rev. 40, 243–288. Gonzalez, F.J., 2005. Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat. Res. 569, 101–110. Gonzalez, F.J., Gelboin, H.V., 1994. Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metab. Rev. 26, 165– 183. Gonzalez, F.J., Ueno, T., Umeno, M., Song, B.J., Veech, R.L., Gelboin, H.V., 1991. Microsomal ethanol oxidizing system: transcriptional and posttranscriptional regulation of cytochrome P450, CYP2E1. Alcohol Alcohol. Suppl. 1, 97–101. Gonzalez, F.J., Yu, A.-M., 2006. Cytochrome P450 and xenobiotic receptor humanized mice. Annu. Rev. Pharmacol. Toxicol. 46, 41–64.

Gross, K.L., Cidlowski, J.A., 2008. Tissue-specific glucocorticoid action: a family affair. Trends Endocrinol. Metab. 19, 331–339. Guengerich, F.P., 1997. Comparisons of catalytic selectivity of cytochrome P450 subfamily enzymes from different species. Chem. Biol. Interact. 106, 161–182. Guengerich, F.P., 2003. Cytochromes P450, drugs, and diseases. Mol. Interv. 3, 194–204. Guengerich, F.P., 2008. Cytochrome p450 and chemical toxicology. Chem. Res. Toxicol. 21, 70–83. Hamilton, K.R., Ansell, E.B., Reynolds, B., Potenza, M.N., Sinha, R., 2013. Self-reported impulsivity, but not behavioral choice or response impulsivity, partially mediates the effect of stress on drinking behavior. Stress 16, 3–15. Handschin, C., Meyer, U.A., 2003. Induction of drug metabolism: the role of nuclear receptors. Pharmacol. Rev. 55, 649–673. Hay, N., 2011. Interplay between FOXO, TOR, and Akt. Biochim. Biophys. Acta 1813, 1965–1970. Helmreich, D.L., Tylee, D., 2011. Thyroid hormone regulation by stress and behavioral differences in adult male rats. Horm. Behav. 60, 284–291. Hollenberg, P.F., 1992. Mechanisms of cytochrome P450 and peroxidase-catalyzed xenobiotic metabolism. FASEB J. 6, 686–694. Holloway, M.G., Laz, E.V., Waxman, D.J., 2006. Codependence of growth hormoneresponsive, sexually dimorphic hepatic gene expression on signal transducer and activator of transcription 5b and hepatic nuclear factor 4alpha. Mol. Endocrinol. 20, 647–660. Holzhutter, H.G., Drasdo, D., Preusser, T., Lippert, J., Henney, A.M., 2012. The virtual liver: a multidisciplinary, multilevel challenge for systems biology. Wiley Interdiscip. Rev. Syst. Biol. Med. 4, 221–235. Honkakoski, P., Negishi, M., 1997. The structure, function, and regulation of cytochrome P450 2A enzymes. Drug Metab. Rev. 29, 977–996. Hukkanen, J., Lassila, A., Paivarinta, K., Valanne, S., Sarpo, S., Hakkola, J., Pelkonen, O., Raunio, H., 2000. Induction and regulation of xenobiotic-metabolizing cytochrome P450s in the human A549 lung adenocarcinoma cell line. Am. J. Respir. Cell Mol. Biol. 22, 360–366. Iber, H., Sewer, M.B., Barclay, T.B., Mitchell, S.R., Li, T., Morgan, E.T., 1999. Modulation of drug metabolism in infectious and inflammatory diseases. Drug Metab. Rev. 31, 29–41. Immink, W.F., Beijer, H.J., Charbon, G.A., 1978. alpha- and beta-receptor blockade of isoproterenol- and norepinephrine-induced effects on regional blood flow and blood flow acceleration. Eur. J. Pharmacol. 50, 159–173. Ingelman-Sundberg, M., 2004a. Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn. Schmiedebergs Arch. Pharmacol. 369, 89–104. Ingelman-Sundberg, M., 2004b. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol. Sci. 25, 193–200. Ingelman-Sundberg, M., Sim, S.C., Gomez, A., Rodriguez-Antona, C., 2007. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol. Ther. 116, 496–526. Johnson, E.O., Kamilaris, T.C., Chrousos, G.P., Gold, P.W., 1992. Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis. Neurosci. Biobehav. Rev. 16, 115–130. Johnson, E.O., Kostandi, M., Moutsopoulos, H.M., 2006. Hypothalamic–pituitary–adrenal axis function in Sjogren’s syndrome: mechanisms of neuroendocrine and immune system homeostasis. Ann. N. Y. Acad. Sci. 1088, 41–51. Jorgensen, E.H., Celander, M., Goksoyr, A., Iwata, M., 2001. The effect of stress on toxicant-dependent cytochrome P450 enzyme responses in the Arctic charr (Salvelinus alpinus). Environ. Toxicol. Chem. 20, 2523–2529. Jover, R., Bort, R., Gomez-Lechon, M.J., Castell, J.V., 2002. Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved. FASEB J. 16, 1799–1801. Kacevska, M., Downes, M.R., Sharma, R., Evans, R.M., Clarke, S.J., Liddle, C., Robertson, G.R., 2011. Extrahepatic cancer suppresses nuclear receptor-regulated drug metabolism. Clin. Cancer Res. 17, 3170–3180. Karasu, S.R., 2012. Of mind and matter: psychological dimensions in obesity. Am. J. Psychother. 66, 111–128. Kato, R., Frontino, G., Vassanellip, 1963. Decreased activities of liver microsomal drug-metabolizing enzymes in the rats bearing Walker carcinosarcoma. Experientia 19, 31–32. Kawajiri, K., 1999. Cyp1a1. IARC Sci. Publ., 159–172. Kennedy, J.M., Riji, A.M., 1998. Effects of surgery on the pharmacokinetic parameters of drugs. Clin. Pharmacokinet. 35, 293–312. Khan, A.A., Chow, E.C., van Loenen-Weemaes, A.M., Porte, R.J., Pang, K.S., Groothuis, G.M., 2009. Comparison of effects of VDR versus PXR, FXR and GR ligands on the regulation of CYP3A isozymes in rat and human intestine and liver. Eur. J. Pharm. Sci. 37, 115–125. Kim, S.K., Novak, R.F., 2007. The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacol. Ther. 113, 88–8120. Kinloch, R.D., Lee, C.M., van Rooijen, N., Morgan, E.T., 2011. Selective role for tumor necrosis factor-alpha, but not interleukin-1 or Kupffer cells, in down-regulation of CYP3A11 and CYP3A25 in livers of mice infected with a noninvasive intestinal pathogen. Biochem. Pharmacol. 82, 312–321. Kivisto, K.T., Niemi, M., Schaeffeler, E., Pitkala, K., Tilvis, R., Fromm, M.F., Schwab, M., Lang, F., Eichelbaum, M., Strandberg, T., 2005. CYP3A5 genotype is associated with diagnosis of hypertension in elderly patients: data from the DEBATE study. Am. J. Pharmacogenomics 5, 191–195.


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Kobayashi, K., Urashima, K., Shimada, N., Chiba, K., 2003. Selectivities of human cytochrome P450 inhibitors toward rat P450 isoforms: study with cDNAexpressed systems of the rat. Drug Metab. Dispos. 31, 833–836. Kobliakov, V., Kulikova, L., Samoilov, D., Lang, M.A., 1993. High expression of cytochrome P450 2a-5 (coumarin 7-hydroxylase) in mouse hepatomas. Mol. Carcinog. 7, 276–280. Konstandi, M., 1996. Effect of cocaine on hepatic drug metabolism. Eur. J. Intern. Med. 7, 221–226. Konstandi, M., 2013. Psychophysiological stress: a significant parameter in drug pharmacokinetics. Expert Opin. Drug Metab. Toxicol. 9, 1317–1334. Konstandi, M., Cheng, J., Gonzalez, F.J., 2013. Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver. Am. J. Physiol. Endocrinol. Metab. 304, E1118–E1128. Konstandi, M., Harkitis, P., Kostakis, D., Marselos, M., Johnson, E.O., Lang, M.A., 2008a. D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1. Life Sci. 82, 1–10. Konstandi, M., Harkitis, P., Thermos, K., Ogren, S.O., Johnson, E.O., Tzimas, P., Marselos, M., 2007. Modification of inherent and drug-induced dopaminergic activity after exposure to benzo(alpha)pyrene. Neurotoxicology 28, 860– 867. Konstandi, M., Johnson, E., Lang, M.A., Camus-Radon, A.M., Marselos, M., 2000a. Stress modulates the enzymatic inducibility by benzo[alpha]pyrene in the rat liver. Pharmacol. Res. 42, 205–211. Konstandi, M., Johnson, E., Lang, M.A., Malamas, M., Marselos, M., 2000b. Noradrenaline, dopamine, serotonin: different effects of psychological stress on brain biogenic amines in mice and rats. Pharmacol. Res. 41, 341–346. Konstandi, M., Johnson, E.O., Marselos, M., Kostakis, D., Fotopoulos, A., Lang, M.A., 2004. Stress-mediated modulation of B(alpha)P-induced hepatic CYP1A1: role of catecholamines. Chem. Biol. Interact. 147, 65–77. Konstandi, M., Kostakis, D., Harkitis, P., Johnson, E.O., Marselos, M., Adamidis, K., Lang, M.A., 2006. Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: role of adrenoceptor-linked signaling pathways. Life Sci. 79, 331–341. Konstandi, M., Kostakis, D., Harkitis, P., Marselos, M., Johnson, E.O., Adamidis, K., Lang, M.A., 2005. Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression. Biochem. Pharmacol. 69, 277–287. Konstandi, M., Kostakis, D., Johnson, E., Lang, M.A., Marselos, M., 1998. Evidence of alpha2-adrenoceptor involvement in B[alpha]P induction processes of drugmetabolizing enzymes: the effect of stress. Eur. J. Drug Metab. Pharmacokinet. 23, 491–495. Konstandi, M., Lang, M.A., Kostakis, D., Johnson, E.O., Marselos, M., 2008b. Predominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyrene. Basic Clin. Pharmacol. Toxicol. 102, 35–44. Konstandi, M., Segos, D., Galanopoulou, P., Theocharis, S., Zarros, A., Lang, M.A., Marselos, M., Liapi, C., 2009. Effects of choline-deprivation on paracetamolor phenobarbital-induced rat liver metabolic response. J. Appl. Toxicol. 29, 101–109. Kot, M., Daniel, W.A., 2011. Cytochrome P450 is regulated by noradrenergic and serotonergic systems. Pharmacol. Res. 64, 371–380. Kotsovolou, O., Ingelman-Sundberg, M., Lang, M.A., Marselos, M., Overstreet, D.H., Papadopoulou-Daifoti, Z., Johanson, I., Fotopoulos, A., Konstandi, M., 2010. Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1075–1084. Kraner, J.C., Lasker, J.M., Corcoran, G.B., Ray, S.D., Raucy, J.L., 1993. Induction of P4502E1 by acetone in isolated rabbit hepatocytes. Role of increased protein and mRNA synthesis. Biochem. Pharmacol. 45, 1483–1492. Krieger, D.T., 1982. Cushing’s syndrome. Monogr. Endocrinol. 22, 1–142. Kyrou, I., Chrousos, G.P., Tsigos, C., 2006. Stress, visceral obesity, and metabolic complications. Ann. N. Y. Acad. Sci. 1083, 77–110. Kyrou, I., Tsigos, C., 2007. Stress mechanisms and metabolic complications. Horm. Metab. Res. 39, 430–438. Kyrou, I., Tsigos, C., 2009. Obesity in the elderly diabetic patient is weight loss beneficial? No. Diabetes Care 32, S403–S409. Lang, N.P., Butler, M.A., Massengill, J., Lawson, M., Stotts, R.C., Hauer-Jensen, M., Kadlubar, F.F., 1994. Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne heterocyclic amines increase the risk for colorectal cancer or polyps. Cancer Epidemiol. Biomarkers Prev. 3, 675–682. Lang, T., Klein, K., Fischer, J., Nussler, A.K., Neuhaus, P., Hofmann, U., Eichelbaum, M., Schwab, M., Zanger, U.M., 2001. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11, 399–415. Lee, S.H., Lee, S.M., 2005. Suppression of hepatic cytochrome P450-mediated drug metabolism during the late stage of sepsis in rats. Shock 23, 144–149. Legraverend, C., Mode, A., Westin, S., Strom, A., Eguchi, H., Zaphiropoulos, P.G., Gustafsson, J.A., 1992. Transcriptional regulation of rat P-450 2C gene subfamily members by the sexually dimorphic pattern of growth hormone secretion. Mol. Endocrinol. 6, 259–266. Leuenberger, N., Pradervand, S., Wahli, W., 2009. Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice. J. Clin. Invest. 119, 3138–3148. Liddle, C., Goodwin, B.J., George, J., Tapner, M., Farrell, G.C., 1998. Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes. J. Clin. Endocrinol. Metab. 83, 2411–2416.

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Liu, C.H., Peck, K., Huang, J.D., Lin, M.S., Wang, C.H., Hsu, W.P., Wang, H.W., Lee, H.L., Lai, M.L., 2005. Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip. Pharmacogenomics 6, 731–747. Liu, Y.T., Hao, H.P., Liu, C.X., Wang, G.J., Xie, H.G., 2007. Drugs as CYP3A probes, inducers, and inhibitors. Drug Metab. Rev. 39, 699–721. Ma, J., Graves, J., Bradbury, J.A., Zhao, Y., Swope, D.L., King, L., Qu, W., Clark, J., Myers, P., Walker, V., Lindzey, J., Korach, K.S., Zeldin, D.C., 2004. Regulation of mouse renal CYP2J5 expression by sex hormones. Mol. Pharmacol. 65, 730–743. Ma, J., Qu, W., Scarborough, P.E., Tomer, K.B., Moomaw, C.R., Maronpot, R., Davis, L.S., Breyer, M.D., Zeldin, D.C., 1999. Molecular cloning, enzymatic characterization, developmental expression, and cellular localization of a mouse cytochrome P450 highly expressed in kidney. J. Biol. Chem. 274, 17777–17788. Mangoni, A.A., Jackson, S.H., 2004. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br. J. Clin. Pharmacol. 57, 6–14. Margolis, R., 2013. Health shocks in the family: gender differences in smoking changes. J. Aging Health 25, 882–903. Martignoni, M., de Kanter, R., Grossi, P., Mahnke, A., Saturno, G., Monshouwer, M., 2004. An in vivo and in vitro comparison of CYP induction in rat liver and intestine using slices and quantitative RT-PCR. Chem. Biol. Interact. 151, 1–11. Martignoni, M., Groothuis, G.M.M., de Kanter, R., 2006. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin. Drug Metab. Toxicol. 2, 875–894. Matamoros, R.A., Levine, B.S., 1996. Stress response and drug metabolism in mice. Fundam. Appl. Toxicol. 30, 255–263. Mayati, A., Levoin, N., Paris, H., N’Diaye, M., Courtois, A., Uriac, P., LagadicGossmann, D., Fardel, O., Le Ferrec, E., 2012. Induction of intracellular calcium concentration by environmental benzo(a)pyrene involves a beta2-adrenergic receptor/adenylyl cyclase/Epac-1/inositol 1,4,5-trisphosphate pathway in endothelial cells. J. Biol. Chem. 287, 4041–4052. McEwen, B.S., 2000. The neurobiology of stress: from serendipity to clinical relevance. Brain Res. 886, 172–189. McMahon, C.D., Chapin, L.T., Radcliff, R.P., Lookingland, K.J., Tucker, H.A., 2001. Somatostatin inhibits alpha-2-adrenergic-induced secretion of growth hormone-releasing hormone. Neuroendocrinology 73, 417–425. Mealy, K., Ngeh, N., Gillen, P., Fitzpatrick, G., Keane, F.B., Tanner, A., 1996. Propranolol reduces the anxiety associated with day case surgery. Eur. J. Surg. 162, 11–14. Meredith, C., Scott, M.P., Renwick, A.B., Price, R.J., Lake, B.G., 2003. Studies on the induction of rat hepatic CYP1A, CYP2B, CYP3A and CYP4A subfamily form mRNAs in vivo and in vitro using precision-cut rat liver slices. Xenobiotica 33, 511–527. Mikhailova, O.N., Gulyaeva, L.F., Filipenko, M.L., 2005. Gene expression of drug metabolizing enzymes in adult and aged mouse liver: a modulation by immobilization stress. Toxicology 210, 189–196. Moreau, A., Vilarem, M.J., Maurel, P., Pascussi, J.M., 2008. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol. Pharm. 5, 35–41. Morris Jr., S.M., Billiar, T.R., 1994. New insights into the regulation of inducible nitric oxide synthesis. Am. J. Physiol. 266, E829–E839. Mulder, G.J., 1994. Interspecies Determinants: Bioactivation and Inactivation of Carcinogens. In: Tardiff, R.G., Lohman, P.H.M., Wogan, G.N. (Eds.), Methods to Assess DNA Damage and Repair: Interspecies Comparisons,. Publisher John Wiley & Sons Ltd. Murray, M., 2006. Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis. Curr. Drug Metab. 7, 67–81. Murray, M., Cantrill, E., Mehta, I., Farrell, G.C., 1992. Impaired expression of microsomal cytochrome P450 2C11 in choline-deficient rat liver during the development of cirrhosis. J. Pharmacol. Exp. Ther. 261, 373–380. Murray, M., Zaluzny, L., Dannan, G.A., Guengerich, F.P., Farrell, G.C., 1987. Altered regulation of cytochrome P-450 enzymes in choline-deficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17dione 16 alpha-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis. Mol. Pharmacol. 31, 117–121. Nadin, L., Butler, A.M., Farrell, G.C., Murray, M., 1995. Pretranslational downregulation of cytochromes P450 2C11 and 3A2 in male rat liver by tumor necrosis factor alpha. Gastroenterology 109, 198–205. Naik, A., Belic, A., Zanger, U.M., Rozman, D., 2013. Molecular interactions between NAFLD and xenobiotic metabolism. Front. Genet. 4, 2. Nebert, D.W., 2000. Suggestions for the nomenclature of human alleles: relevance to ecogenetics, pharmacogenetics and molecular epidemiology. Pharmacogenetics 10, 279–290. Nebert, D.W., Nelson, D.R., Coon, M.J., Estabrook, R.W., Feyereisen, R., Fujii-Kuriyama, Y., Gonzalez, F.J., Guengerich, F.P., Gunsalus, I.C., Johnson, E.F., et al., 1991a. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol. 10, 1–14. Nebert, D.W., Petersen, D.D., Puga, A., 1991b. Human AH locus polymorphism and cancer: inducibility of CYP1A1 and other genes by combustion products and dioxin. Pharmacogenetics 1, 68–78. Nebert, D.W., Russell, D.W., 2002. Clinical importance of the cytochromes P450. Lancet 360, 1155–1162. Nebert, D.W., Wikvall, K., Miller, W.L., 2013. Human cytochromes P450 in health and disease. Philos. Trans. R. Soc. Lond. B: Biol. Sci. 368, 20120431. Nelson, D.R., 2009. The cytochrome P450 homepage. Hum. Genom. 4, 59–65. Nelson, D.R., Kamataki, T., Waxman, D.J., Guengerich, F.P., Estabrook, R.W., Feyereisen, R., Gonzalez, F.J., Coon, M.J., Gunsalus, I.C., Gotoh, O., et al., 1993. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 12, 1–51.


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G Model NBR 1957 1–19 18 1817 1818 1819 1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 1842 1843 1844 1845 1846 1847 1848 1849 1850 1851 1852 1853 1854 1855 1856 1857 1858 1859 1860 1861 1862 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 1873 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894 1895 1896 1897 1898 1899 1900 1901 1902


Newton, D.J., Wang, R.W., Lu, A.Y., 1995. Cytochrome P450 inhibitors. Evaluation of specificities in the in vitrometabolism of therapeutic agents by human liver microsomes. Drug Metab. Dispos. 23, 154–158. Niznik, H.B., Tyndale, R.F., Sallee, F.R., Gonzalez, F.J., Hardwick, J.P., Inaba, T., Kalow, W., 1990. The dopamine transporter and cytochrome P45OIID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR12935 binding proteins. Arch. Biochem. Biophys. 276, 424–432. Novak, R.F., Woodcroft, K.J., 2000. The alcohol-inducible form of cytochrome P450 (CYP 2E1): role in toxicology and regulation of expression. Arch. Pharm. Res. 23, 267–282. Oh, S.J., Choi, J.M., Yun, K.U., Oh, J.M., Kwak, H.C., Oh, J.G., Lee, K.S., Kim, B.H., Heo, T.H., Kim, S.K., 2012. Hepatic expression of cytochrome P450 in type 2 diabetic Goto-Kakizaki rats. Chem. Biol. Interact. 195, 173–179. Ohashi, Y., Yamada, K., Takemoto, I., Mizutani, T., Saeki, K., 2005. Inhibition of human cytochrome P450 2E1 by halogenated anilines, phenols, and thiophenols. Biol. Pharm. Bull. 28, 1221–1223. Okey, A.B., 1990. Enzyme induction in the cytochrome P-450 system. Pharmacol. Ther. 45, 241–298. Overstreet, D.H., 2012. Modeling depression in animal models. Methods Mol. Biol. 829, 125–144. Overstreet, D.H., Friedman, E., Mathe, A.A., Yadid, G., 2005. The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci. Biobehav. Rev. 29, 739–759. Pampori, N.A., Shapiro, B.H., 1999. Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile. Endocrinology 140, 1245–1254. Pasanen, M., Pelkonen, O., 1994. The expression and environmental regulation of P450 enzymes in human placenta. Crit. Rev. Toxicol. 24, 211–229. Pascussi, J.M., Drocourt, L., Gerbal-Chaloin, S., Fabre, J.M., Maurel, P., Vilarem, M.J., 2001. Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor. Eur. J. Biochem. 268, 6346–6358. Pascussi, J.M., Gerbal-Chaloin, S., Drocourt, L., Assenat, E., Larrey, D., Pichard-Garcia, L., Vilarem, M.J., Maurel, P., 2004. Cross-talk between xenobiotic detoxication and other signalling pathways: clinical and toxicological consequences. Xenobiotica 34, 633–664. Pascussi, J.M., Gerbal-Chaloin, S., Drocourt, L., Maurel, P., Vilarem, M.J., 2003. The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim. Biophys. Acta 1619, 243–253. Pascussi, J.M., Gerbal-Chaloin, S., Pichard-Garcia, L., Daujat, M., Fabre, J.M., Maurel, P., Vilarem, M.J., 2000. Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. Biochem. Biophys. Res. Commun. 274, 707–713. Pascussi, J.M., Vilarem, M.J., 2008. [[Inflammation and drug metabolism: NF-kappB and the CAR and PXR xeno-receptors]. Med. Sci. (Paris) 24, 301–305. Pavek, P., Cerveny, L., Svecova, L., Brysch, M., Libra, A., Vrzal, R., Nachtigal, P., Staud, F., Ulrichova, J., Fendrich, Z., Dvorak, Z., 2007. Examination of glucocorticoid receptor alpha-mediated transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 genes in placental trophoblast cell lines. Placenta 28, 1004–1011. Pelkonen, O., Raunio, H., 1997. Metabolic activation of toxins: tissue-specific expression and metabolism in target organs. Environ. Health Perspect. 105 (Suppl. 4), 767–774. Pelkonen, O., Rautio, A., Raunio, H., Pasanen, M., 2000. CYP2A6: a human coumarin 7-hydroxylase. Toxicology 144, 139–147. Pelkonen, O., Turpeinen, M., Hakkola, J., Honkakoski, P., Hukkanen, J., Raunio, H., 2008. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch. Toxicol. 82, 667–715. Peng, H.T., Cheung, B., 2011. A review of psychophysiological stressors on pharmacokinetics. J. Clin. Pharmacol. 51, 1499–1518. Pervanidou, P., Chrousos, G.P., 2012. Metabolic consequences of stress during childhood and adolescence. Metabolism. 61, 611–619. Pervanidou, P., Margeli, A., Lazaropoulou, C., Papassotiriou, I., Chrousos, G.P., 2008. The immediate and long-term impact of physical and/or emotional stress from motor vehicle accidents on circulating stress hormones and adipo-cytokines in children and adolescents. Stress 11, 438–447. Plotsky, P.M., 1987. Facilitation of immunoreactive corticotropin-releasing factor secretion into the hypophysial-portal circulation after activation of catecholaminergic pathways or central norepinephrine injection. Endocrinology 121, 924–930. Powell, N.D., Tarr, A.J., Sheridan, J.F., 2013. Psychosocial stress and inflammation in cancer. Brain Behav. Immun. 30 (Suppl.), S41–S47. Prasad, B.M., Sorg, B.A., Ulibarri, C., Kalivas, P.W., 1995. Sensitization to stress and psychostimulants. Involvement of dopamine transmission versus the HPA axis. Ann. N. Y. Acad. Sci. 771, 617–625. Ram, P.A., Waxman, D.J., 1991. Hepatic P450 expression in hypothyroid rats: differential responsiveness of male-specific P450 forms 2a (IIIA2), 2c (IIC11), and RLM2 (IIA2) to thyroid hormone. Mol. Endocrinol. 5, 13–20. Raucy, J.L., Lasker, J.M., Kraner, J.C., Salazar, D.E., Lieber, C.S., Corcoran, G.B., 1991. Induction of cytochrome P450IIE1 in the obese overfed rat. Mol. Pharmacol. 39, 275–280. Rendic, S., Guengerich, F.P., 2010. Update information on drug metabolism systems—2009, part II: summary of information on the effects of diseases and environmental factors on human cytochrome P450 (CYP) enzymes and transporters. Curr. Drug Metab. 11, 4–84. Rentesi, G., Antoniou, K., Marselos, M., Syrrou, M., Papadopoulou-Daifoti, Z., Konstandi, M., 2013. Early maternal deprivation-induced modifications in the

neurobiological, neurochemical and behavioral profile of adult rats. Behav. Brain Res. 244, 29–37. Robottom-Ferreira, A.B., Aquino, S.R., Queiroga, R., Albano, R.M., Ribeiro Pinto, L.F., 2003. Expression of CYP2A3 mRNA and its regulation by 3-methylcholanthrene, pyrazole, and beta-ionone in rat tissues. Braz. J. Med. Biol. Res. 36, 839–844. Roman, R.J., 2002. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev. 82, 131–185. Rostami-Hodjegan, A., Tucker, G.T., 2007. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat. Rev. Drug Discov. 6, 140–148. Roymans, D., Annaert, P., Van Houdt, J., Weygers, A., Noukens, J., Sensenhauser, C., Silva, J., Van Looveren, C., Hendrickx, J., Mannens, G., Meuldermans, W., 2005. Expression and induction potential of cytochromes P450 in human cryopreserved hepatocytes. Drug Metab. Dispos. 33, 1004–1016. Salaspuro, M.P., Lieber, C.S., 1978. Non-uniformity of blood ethanol elimination: its exaggeration after chronic consumption. Ann. Clin. Res. 10, 294–297. Satoh, M., Nakamura, M., Saitoh, H., Satoh, H., Akatsu, T., Iwasaka, J., Masuda, T., Hiramori, K., 2002. Aldosterone synthase (CYP11B2) expression and myocardial fibrosis in the failing human heart. Clin. Sci. (Lond.) 102, 381–386. Schule, C., Baghai, T., Laakmann, G., 2004. Mirtazapine decreases stimulatory effects of reboxetine on cortisol, adrenocorticotropin and prolactin secretion in healthy male subjects. Neuroendocrinology 79, 54–62. Sheiner, L.B., Steimer, J.L., 2000. Pharmacokinetic/pharmacodynamic modeling in drug development. Annu. Rev. Pharmacol. Toxicol. 40, 67–95. Shimada, T., Guengerich, F.P., 1989. Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver. Proc. Natl. Acad. Sci. U. S. A. 86, 462–465. Shimada, T., Mimura, M., Inoue, K., Nakamura, S., Oda, H., Ohmori, S., Yamazaki, H., 1997. Cytochrome P450-dependent drug oxidation activities in liver microsomes of various animal species including rats, guinea pigs, dogs, monkeys, and humans. Arch. Toxicol. 71, 401–408. Shimada, T., Yamazaki, H., Foroozesh, M., Hopkins, N.E., Alworth, W.L., Guengerich, F.P., 1998. Selectivity of polycyclic inhibitors for human cytochrome P450s 1A1, 1A2, and 1B1. Chem. Res. Toxicol. 11, 1048–1056. Shou, M., Krausz, K.W., Gonzalez, F.J., Gelboin, H.V., 1996. Metabolic activation of the potent carcinogen dibenzo[a,l]pyrene by human recombinant cytochromes P450, lung and liver microsomes. Carcinogenesis 17, 2429–2433. Sigel, A., Sigel, H., Sigel, R.K.O., 2007. The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences. Wiley. Spanagel, R., Montkowski, A., Allingham, K., Stohr, T., Shoaib, M., Holsboer, F., Landgraf, R., 1995. Anxiety: a potential predictor of vulnerability to the initiation of ethanol self-administration in rats. Psychopharmacology (Berl.) 122, 369–373. Spatzenegger, M., Jaeger, W., 1995. Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab. Rev. 27, 397–417. Stranger, B.E., Forrest, M.S., Dunning, M., Ingle, C.E., Beazley, C., Thorne, N., Redon, R., Bird, C.P., de Grassi, A., Lee, C., Tyler-Smith, C., Carter, N., Scherer, S.W., Tavare, S., Deloukas, P., Hurles, M.E., Dermitzakis, E.T., 2007. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853. Sugimura, T., Sato, S., 1983. Mutagens-carcinogens in foods. Cancer Res. 43, 2415s–2421s. Swain, M.G., 2000. I. Stress and hepatic inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G1135–G1138. Synold, T.W., Dussault, I., Forman, B.M., 2001. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat. Med. 7, 584–590. Takahashi, N., Inui, N., Morita, H., Takeuchi, K., Uchida, S., Watanabe, H., Nakamura, H., 2010. Effect of thyroid hormone on the activity of CYP3A enzyme in humans. J. Clin. Pharmacol. 50, 88–93. Tan, F.L., Moravec, C.S., Li, J., Apperson-Hansen, C., McCarthy, P.M., Young, J.B., Bond, M., 2002. The gene expression fingerprint of human heart failure. Proc. Natl. Acad. Sci. U. S. A. 99, 11387–11392. Tsigos, C., Chrousos, G.P., 2002. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J. Psychosom. Res. 53, 865–871. Tuomisto, J., Mannisto, P., 1985. Neurotransmitter regulation of anterior pituitary hormones. Pharmacol. Rev. 37, 249–332. Vere, C.C., Streba, C.T., Streba, L.M., Ionescu, A.G., Sima, F., 2009. Psychosocial stress and liver disease status. World J. Gastroenterol. 15, 2980–2986. Vuppugalla, R., Shah, R.B., Chimalakonda, A.P., Fisher, C.W., Mehvar, R., 2003. Microsomal cytochrome P450 levels and activities of isolated rat livers perfused with albumin. Pharm. Res. 20, 81–88. Waller, D., Renwick, A.G., Hillier, K., 2005. Medical Pharmacology and Therapeutics. Elsevier Saunders. Warren, G.W., Poloyac, S.M., Gary, D.S., Mattson, M.P., Blouin, R.A., 1999. Hepatic cytochrome P-450 expression in tumor necrosis factor-alpha receptor (p55/p75) knockout mice after endotoxin administration. J. Pharmacol. Exp. Ther. 288, 945–950. Warren, G.W., van Ess, P.J., Watson, A.M., Mattson, M.P., Blouin, R.A., 2001. Cytochrome P450 and antioxidant activity in interleukin-6 knockout mice after induction of the acute-phase response. J. Interferon Cytokine Res. 21, 821–826. Wastl, U.M., Rossmanith, W., Lang, M.A., Camus-Randon, A.M., Grasl-Kraupp, B., Bursch, W., Schulte-Hermann, R., 1998. Expression of cytochrome P450 2A5 in preneoplastic and neoplastic mouse liver lesions. Mol. Carcinog. 22, 229–234. Waxman, D.J., Holloway, M.G., 2009. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol. Pharmacol. 76, 215–228. Waxman, D.J., Pampori, N.A., Ram, P.A., Agrawal, A.K., Shapiro, B.H., 1991. Interpulse interval in circulating growth hormone patterns regulates sexually


1903 1904 1905 1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 1916 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988



1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

dimorphic expression of hepatic cytochrome P450. Proc. Natl. Acad. Sci. U. S. A. 88, 6868–6872. Wiwi, C.A., Waxman, D.J., 2004. Role of hepatocyte nuclear factors in growth hormone-regulated, sexually dimorphic expression of liver cytochromes P450. Growth Factors 22, 79–88. Woodcroft, K.J., Hafner, M.S., Novak, R.F., 2002. Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. Hepatology 35, 263–273. Woodcroft, K.J., Novak, R.F., 1997. Insulin effects on CYP2E1, 2B, 3A, and 4A expression in primary cultured rat hepatocytes. Chem. Biol. Interact. 107, 75–91. Wu, D., Cederbaum, A.I., 2003. Alcohol, oxidative stress, and free radical damage. Alcohol Res. Health 27, 277–284. Xie, W., Evans, R.M., 2001. Orphan nuclear receptors: the exotics of xenobiotics. J. Biol. Chem. 276, 37739–37742. Xu, M., Nelson, G.B., Moore, J.E., McCoy, T.P., Dai, J., Manderville, R.A., Ross, J.A., Miller, M.S., 2005. Induction of Cyp1a1 and Cyp1b1 and formation of DNA adducts in C57BL/6, Balb/c, and F1 mice following in utero exposure to 3methylcholanthrene. Toxicol. Appl. Pharmacol. 209, 28–38. Yamaura, Y., Yoshinari, K., Yamazoe, Y., 2011. Predicting oxidation sites with order of occurrence among multiple sites for CYP4A-mediated reactions. Drug Metab. Pharmacokinet. 26, 351–363. Yates, F.E., Marsh, D.J., Maran, J.W., 1980. The Adrenal Cortex. In: Mountcastle, V.B. (Ed.), Medical Physiology. , pp. 1558–1601. Yoo, J.S., Hong, J.Y., Ning, S.M., Yang, C.S., 1990. Roles of dietary corn oil in the regulation of cytochromes P450 and glutathione S-transferases in rat liver. J. Nutr. 120, 1718–1726. Yoo, J.S., Smith, T.J., Ning, S.M., Lee, M.J., Thomas, P.E., Yang, C.S., 1992. Modulation of the levels of cytochromes P450 in rat liver and lung by dietary lipid. Biochem. Pharmacol. 43, 2535–2542.

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Yu, R., Lei, W., Mandlekar, S., Weber, M.J., Der, C.J., Wu, J., Kong, A.N., 1999. Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J. Biol. Chem. 274, 27545–27552. Yun, K., 1992. A new marker for rhabdomyosarcoma. Insulin-like growth factor II. Lab. Invest. 67, 653–664. Zanger, U.M., Raimundo, S., Eichelbaum, M., 2004. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn. Schmiedebergs Arch. Pharmacol. 369, 23–37. Zanger, U.M., Schwab, M., 2013. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 138, 103–141. Zeldin, D.C., 2001. Epoxygenase pathways of arachidonic acid metabolism. J. Biol. Chem. 276, 36059–36062. Zhang, W., Parentau, H., Greenly, R.L., Metz, C.A., Aggarwal, S., Wainer, I.W., Tracy, T.S., 1999. Effect of protein-calorie malnutrition on cytochromes P450 and glutathione S-transferase. Eur. J. Drug Metab. Pharmacokinet. 24, 141–147. Zhou, S.-F., Liu, J.-P., Chowbay, B., 2009a. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab. Rev. 41, 89–8295. Zhou, S.-F., Xue, C.C., Yu, X.-Q., Li, C., Wang, G., 2007. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther. Drug Monit. 29, 687– 710. Zhou, S.F., Zhou, Z.W., Yang, L.P., Cai, J.P., 2009b. Substrates, inducers, inhibitors and structure–activity relationships of human cytochrome P450 2C9 and implications in drug development. Curr. Med. Chem. 16, 3480–3675. Zordoky, B.N., El-Kadi, A.O., 2009. Role of NF-kappaB in the regulation of cytochrome P450 enzymes. Curr. Drug Metab. 10, 164–178. Zuber, R., Anzenbacherova, E., Anzenbacher, P., 2002. Cytochromes P450 and experimental models of drug metabolism. J. Cell. Mol. Med. 6, 189–198.


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