Opportunities and challenges in using human hepatocytes in cytochromes P450 induction assays.

Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20

Opportunities and challenges in using human hepatocytes in cytochrome P450 induction assays Zdenek Dvorak To cite this article: Zdenek Dvorak (2015): Opportunities and challenges in using human hepatocytes in cytochrome P450 induction assays, Expert Opinion on Drug Metabolism & Toxicology, DOI: 10.1517/17425255.2016.1125881 To link to this article: http://dx.doi.org/10.1517/17425255.2016.1125881

Accepted author version posted online: 27 Nov 2015.

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Date: 04 December 2015, At: 00:32

PUBLISHER: TAYLOR & FRANCIS JOURNAL: EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY DOI: 10.1517/17425255.2016.1125881

OPPORTUNITIES AND CHALLENGES IN USING HUMAN HEPATOCYTES IN CYTOCHROME P450

Downloaded by [University of California, San Diego] at 00:32 04 December 2015

INDUCTION ASSAYS

Zdenek Dvorak Department of Cell Biology and Genetics Faculty of Science, Palacky University Olomouc Slechtitelu 27, Olomouc 783 71 Czech Republic Tel: +420-58-563-4901

Fax: +420-58-563-4901

Email: [email protected]

ABSTRACT Introduction: Identification of inducers of xenobiotic-metabolizing cytochrome P450s is of topical interest. The issue mainly concerns three sectors: (i) pre-clinical testing of drug candidates and testing existing drugs and their combinations; (ii) food safety applications with regards to additives, contaminants and adulterants; (iii) environmental applications, comprising detection and identification of endocrine disruptors. Areas covered: A literature search was performed using the PubMed database, covering state-of-the-art of human hepatocyte (HHs) culture use, and their exploitation for identification of P450s inducers. A list of CYPs inducers identified by HHs is provided.

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Expert opinion: Primary cultures of HHs had long been considered as a gold standard for induction assays of xenobiotic-metabolizing enzymes. Owing to several shortcomings of HHs, alternative approaches such as immortalization of HHs, use of cell lines, generation of clonal cell lines from HHs, use of iPS, cells from humanized animals etc. were employed. While yielding particular advantage, overall, alternatives to HHs still remain an avenue for discrete applications or technical situations. Thus, HHs remain the most suitable model for


complex CYP induction studies. The summary may be effectively expressed by SWOT analysis.

Keywords: drug-drug interactions; drug-metabolizing enzymes; gene induction; human hepatocytes

Article highlights box: •

Human hepatocytes HHs are the gold standard for induction assays of xenobiotic metabolizing P450s

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HHs provide the opportunity to study induction of phase II enzymes and xenobiotics transporters

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HHs have complex signaling and metabolizing pathways, providing highly physiological model

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HHs allow studying the effects of metabolites and maternal drugs simultaneously

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HHs avoid interspecies differences, which are important in induction process

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1. INTRODUCTION Metabolism of drugs and other xenobiotics in humans occurs dominantly in liver, but also in several extrahepatic tissues including intestine, lungs, skin, placenta etc. An integral part of xenobiotics metabolism is so called Phase I., which is also referred as to oxido-reductive & hydrolytic phase. The purpose of Phase I. is to increase the polarity of xenobiotic by the


means of introduction of polar group in the molecule, conversion of less polar group to more polar one, or by unmasking the polar group by hydrolysis. The major role in Phase I. oxidoreductive reactions plays a superfamily of drug-metabolizing enzymes cytochromes P450 (CYPs). Biotransformation of xenobiotics is inseparable from a phenomenon called drug-drug interactions, which means that ultimate effect of drug #1 is influenced by the presence of drug #2. Clinically relevant pharmacokinetic drug-drug interactions involving cytochromes P450 occur by two main mechanisms: (i) The inhibition of particular CYP or the competition for CYP by the drug [1, 2]; (ii) The induction of particular CYP by the drug = the topic of the current paper [3]. The induction of drug-metabolizing CYPs by xenobiotics, i.e. de novo protein synthesis, is mediated through several ligand-activated transcriptional factors, including: (i) Xenoreceptors: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR); (ii) Steroid receptors: glucocorticoid receptor (GR), estrogen receptor (ER); (iii) Nuclear receptors: vitamin D receptor (VDR), retinoic acid receptors (RARs), retinoic X receptors (RXRs), hepatocyte nuclear factor 4 1 (HNF4 1), peroxisome proliferator-activated receptors (PPARs). Ligand-receptor complex binds to its cognate DNAbinding sequence in CYP promoter and gene transcription is triggered resulting in classical axis CYP mRNA – CYP protein - functional CYP enzyme. It is worth to emphasize that 3

xenoreceptors mediate transcriptional regulation of drug-metabolizing CYPs, but also of many other enzymes and genes involved in intermediary cell metabolism, such as CYPs participating in metabolism of steroid hormones (CYP17A1) cholesterol (CYP46A1), eicosanoids (CYP4A11, CYP4F2), vitamin D (CYP24A1) or retinoids (CYP26A1). Vice versa, steroid and nuclear receptors are important transcriptional regulators of drugmetabolizing CYPs [4-7].


Unlike pharmacodynamic drug-drug interactions, pharmacokinetic ones are not principally foreseeable and appropriate experimental tools are needed to predict and prevent them. The existing experimental approaches are extensive. The first issue is the choice of species. While induction studies on xenobiotics vs P450s were carried out in many species, including rodents (mouse, rat, guinea pig), aquatic organisms (zebrafish, rainbow trout, catfish), pig, cat, dog, chicken, camel etc., for the purposes of studies related to drug-drug interactions, environmental exposure or food safety, the human models remain the systems of choice. The reasons are multiple, including interspecies differences in CYP nomenclature, substrate specificity or transcriptional regulation. The second issue is the complexity of the experimental models. The model with highest degree of integrity for human studies is a man, which is exploitable in late stages of clinical studies. The opposite model, regarding the complexity, is perhaps isolated biomacromolecule (e.g. nuclear receptor), often only ligandbinding sequence, and the interaction between xenobiotic and the molecule is either directly measured, or studied in silico. Between these two extremes in complexity, the large number of experimental models exists, including perfused organs, tissue cultures, tissue slices, cell suspensions or adherent cells in various spatial arrangements etc. The choice of model according to its integrity depends on multiple parameters, including the number of tested compounds, the time schedule of experiments, or the purpose of the study. Human hepatocytes (HHs) are highly complex experimental system, representing closely liver

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physiology and pathophysiology. On the other hand, it is still classical in vitro model, raising minimal ethical issues. The following section will deal with the model of human hepatocytes for induction studies of cytochrome P450 by xenobiotics.

2. BODY 2.1. Source of human hepatocytes


The only source of human hepatocytes is the liver from alive human (i.e. not post mortem). Acquisition of liver tissue raises ethical issues that are addressed in compliance with national laws [8, 9]. Liver tissue for preparation of human hepatocytes is obtained from surplus tissue obtained from small liver biopsies or partial hepatectomies carried out for medical purposes unrelated to human hepatocytes research. The weakness of such a source is that liver tissue may be contaminated or afflicted by a pathology for which the medical intervention was carried out (e.g. cancer, cirrhosis, hepatitis, alcoholic liver disease etc.). Another source of liver tissue is from multiorgan donors, i.e. from patients diagnosed for brain death, still having organs such as kidney, heart, liver, lung etc. vital and in condition suitable for transplantation. In case that there was not found recipient for liver from multiorgan donor, the organ could be used for research purposes. With increasing capabilities in terms of transportation, networking and communication between medical centers, the livers from transplant patients for isolation of human hepatocytes are scarce. On the other hand, such a liver is healthy, without pathological burden.

2.2. Storage and maintenance of human hepatocytes A specific feature of human hepatocytes is that they are terminally differentiated cells, which do not proliferate in vitro. Therefore, once isolated, a great challenge is to store human hepatocytes. Enormous efforts were expended for development and optimization of

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cryopreservation procedures. Nowadays, cryopreserved human hepatocytes for induction studies cytochrome P450 are commercially available [10, 11]. The disadvantage of cryopreserved hepatocytes is their limited amount for experiments, because cryotube contains usually about 2 mL of cell suspension, giving limited number of attached viable cells. Novel research directions deal with long-term cold preservation of human hepatocytes, which are intended also for liver cell biotherapy [12]. The second shortcoming of human hepatocytes in


primary culture is their dedifferentiation, which means that they lose their hepatospecific functions with increasing time in culture. So called short-term cultures of human hepatocytes are exploitable for induction studies up to 10-14 days upon their isolation. Several culture protocols were developed to allow human hepatocytes in primary culture remain fully functional for long periods of time, allowing induction studies over 2 months in culture [13].

2.3. Experimental models of human hepatocytes Hepatocytes in stirred suspensions may be used only for short-term, often metabolic, experiments, lasting few hours. The majority of cytochrome P450 induction assays in human hepatocytes is carried out in the monolayers, so called primary cultures of human hepatocytes, which are attached usually on collagen-coated plastic ware. Various spatial arrangements were developed and invented in laboratories, having particular advantages over primary cultures, but often compensated by loss of comfort during experimentation and some trouble shootings. For instance, induction studies were performed in sandwich cultures (mimics passage of xenobiotics through extra-cellular matrix) [14, 15], in various 3D arrangements including in matrigel (mimics spatial situation in liver) [16, 17], and in various arrangements using immobilized cells – bioreactors (mimics blood stream flow) [18].

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2.4. Alternative models to human hepatocytes Various approaches were applied in order to design and developed alternative models to “classical primary human hepatocytes: (i) In vitro, isolated hepatocytes do not longer retain their proliferative capacity, but cell growth can be boosted by immortalization of hepatocytes. Well-defined immortalization genes can be artificially overexpressed in hepatocytes or the


cells can be conditionally immortalized leading to controlled cell proliferation [19]. However, limitations of immortalized human hepatocytes as predictive tool for CYP induction studies were reported [20]. Differentiation and proliferative activity of human hepatocytes in primary culture rapidly declines with increasing time; interestingly this decline is slower in cell from juvenile donors as compared to adult ones [21]. Several studies were engaged to search for culture conditions, which could restart and maintain proliferation and differentiation state of human hepatocytes, however, without substantial success [22]. Human fetal liver cells can be easily expanded in vitro, however, they have decreased hepatic functionality [23]. Highly promising alternative to adult primary human hepatocytes are hepatic-like cells obtained from liver progenitor cells or stem cells. Non-parenchymal epithelial cells were isolated from adult human liver and then cultured at confluence in the presence of hepatocyte growth factor, epidermal growth factor and fibroblast growth factor-4. Cells entered a differentiation process toward hepatocytes and their phenotype was quantitatively compared with that of mature human hepatocytes in primary culture [24, 25]. Human induced pluripotent stem (iPS) cells can be efficiently induced to differentiate into hepatocyte-like cells [26-28], which were described as suitable models for testing hepatocellular acute toxicity of xenobiotics [29], chronic toxicity [30], liver injury [31], and which retained the xenobiotics-mediated induction of drug-metabolizing enzymes [32]. Recently, it was demonstrated that iPS cells derived hepatocyte-like cells retain donor-specific cytochrome P450 metabolism capacity and drug

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responsiveness, therefore, reflecting the interindividual differences in that aspect [33]. The attempts regarding stability of iPS-derived hepatocytes were made [34]. Similarly like iPS, also hepatocytes derived from human embryonic stem cells (hESC) were functional in the aspects described above [28]. Liver progenitor cell line HepaRG was isolated from an Edmonson grade I differentiated liver tumor that developed macronodular cirrhosis resulting from long-term chronic HCV infection [35]. Basal activities of P450s and their response to


prototypical inducers revealed the functional resemblance of HepaRG cells to primary cultured human hepatocytes [36]. Several ongoing studies confirmed that HepaRG represent a reliable surrogate to human hepatocytes for drug metabolism and toxicity studies and for prediction of induction of drug-metabolizing P450 enzymes in vivo in humans [37, 38]. Recently, the usefulness of isolated human hepatocytes from chimeric mice was demonstrated for metabolism and induction studies of xenobiotics and HBV-infection studies [39-41].

2.5. Human hepatocytes in primary culture for xenobiotic-metabolizing P450s induction studies Standard protocols were elaborated for the treatments and cultivation of primary human hepatocytes to evaluate the capability of xenobiotic to induce drug-metabolizing P450s. It is worth mentioning several aspects regarding such the assays: (i) There is a substantial interindividual variability between primary cultures prepared from different donors. Therefore, induction studies have to be performed in several primary cultures from different donors (at least at 3 cultures; usually in 5 – 10 cultures). The interindividual differences are often due to the gene polymorphism of cytochromes P450, their transcriptional regulators, drug transporters and phase II enzymes. It implies that the race of donor, and hence relative frequency of polymorphism in this race, contribute to overall interindividual variability. There are also many physiological (age, sex, pregnancy) and pathophysiological (obesity, diabetes,

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cancer, inflammation, infection) factors contributing to interindividual variability [42-44]. (ii) Human hepatocytes are fully metabolically competent cells; therefore, an assessment of xenobiotics capability to induce P450s involves not only the effects of maternal compound, but also the effects of its phase I and phase II metabolites. The absence of metabolites in the culture medium of various liver-derived cancer cells (e.g. HepG2), is the major difference as compared to human hepatocytes, resulting potentially in both false negative and/or false


positive data [45, 46]. (iii) Standard protocols were elaborated for induction studies in primary human hepatocytes. Briefly, following the seeding of hepatocytes, they are allowed to stabilize for about 48 h - 72 h. During this period, basal level of xenobiotic-inducible CYPs drops drastically; hence, the magnitude of induction as compared to control cells increase substantially. Incubation of hepatocytes with tested compounds is carried out in serum-free medium. Medium including tested compounds (usually dissolved in DMSO as vehicle) are exchanged every day during the treatment. The time of incubation depends on measured endpoint for induction. For measurement of mRNA, hepatocytes are incubated with xenobiotic either for 4 h – 12 h to assess dynamics of de novo transcription, or for 24 h – 48 h to assess gross effect of xenobiotic plus its metabolites. Expression of CYP proteins, and catalytic activity of CYP enzymes is usually evaluated after 48 h – 96 h of incubation with tested compounds. Accordingly, the data have to be properly interpreted; e.g. induction of CYP mRNA is rather of mechanistic importance, while substantial decline in CYP catalytic activity is potentially of clinical relevance [47, 48]. Indeed, a bad correlation was reported between the induction of CYP mRNA and the induction of CYP catalytic activity in HHs [49]. (iv) Identification of CYPs inducers using human hepatocytes: An extensive literature search for articles dealing with CYPs induction by xenobiotics in human hepatocytes was performed using PubMed database. Over 600 articles were carefully analyzed, and the exhaustive list of inducers and repressors of xenobiotics-metabolizing CYPs, which were identified by assays in

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both freshly prepared and cryopreserved human hepatocytes is provided in Supplemental Table 1. The list does not include: (a) Articles that presented negative effects (no induction of CYPs) by new drugs candidates as well as existing drugs and xebobiotics; (b) Studies involving herbal extracts, environmental samples and another mixtures; (c) Comparative studies, i.e. between the models, species, cell lines etc.


3. EXPERT OPINION Primary cultures of human hepatocytes had long been considered as a gold standard for induction assays of xenobiotic-metabolizing enzymes. Owing to several shortcomings of HHs, alternative approaches such as immortalization of HHs, use of cell lines, generation of clonal cell lines from HHs, use of iPS, cells from humanized animals etc. were employed. While yielding particular advantage, overall, alternatives to HHs still remain an avenue for discrete applications or technical situations. The extensive efforts are made concerning the use of HHs for other purposes than induction studies, in particular, in liver biotherapy and in (patho-)physiological studies. Thus, human hepatocytes still remain to be the most suitable model for complex CYPs induction studies. The summary may be effectively expressed by SWOT analysis. 3.1 Strengths Human hepatocytes are per se the model that overcomes complications with interspecies variability, without need to extrapolate the data from animals to man. HHs are highly physiological system in comparison with other cellular liver systems derived from cancer or transformed cells. HHs possess complex and integrate biotransformation machinery, including phase I and phase II enzymes, and full panel of drug transporters. Therefore HHs are reliable and efficient model for performing metabolic studies. 3.2 Weaknesses

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Significant drawback in use of HHs is their scarcity in both time and quantity. With improvement of networks between transplant centers and with patient-friendly surgery techniques, the availability of HHs diminished. It is also inter-individual variability between HHs obtained from different patients, which brings necessity of experimentation in several HHs cultures, thus, making use of HHs time- and material-demanding. 3.3 Opportunities


A great challenge in the field of experimentation with HHs is the optimization and improvement of storage and maintenance conditions. In particular, techniques allowing cryopreservation of significant amount of HHs would resolve the weakness given by scarcity of HHs. While current approaches are developed for cryopreservation of millions of HHs in milliliters of volume, really new-epoque-making invention would be the technique allowing freeze/thaw billions of HHs in one batch. Improvement of networking between clinics and researchers may be considered not only as weakness leading to diminished number of liver available for research purposes, but contrary it may result in more effective exploitation of liver sources, and increase of available experimental material. 3.4 Threats Considerable risks for the use of human liver for isolation of HHs stem from ethical considerations, including the protection of personal data regarding genomic experiments. These treats are strongly bound to legislation of individual states, hence, making current limitations and future risks dependent on the country of interest.

Declaration of Interest The author was supported by grants from the Czech Science Foundation GACR 303/12/G163 and Ministry of Health of the Czech Republic NT/13591. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. 11

Bibliography Papers of special note have been highlighted as: * of interest ** of considerable interest


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Supplemental Table 1. LIST OF COMPOUNDS IDENTIFIED AS INDUCERS OR REPRESSORS OF XENOBIOTICS-METABOLIZING CYTOCHROMES P450 IN HUMAN HEPATOCYTES CULTURES


*Only chemical individuals are listed – i.e. not extracts, mixtures etc.

COMPOUND Reference

CYP induced/repressed

A-792611 (HIV protease inhibitor) [1] 1α,25-di-OH-vitamin D3 [2, 3] 2-ACETYLAMINOFLUORENE [4] ADZ7325 (GABA receptor modulator) [5] AFLATOXIN B1 [6] ALACHLOR [7] ALLOCRYPTOPINE [8] 1-AMINOBENZTRIAZOL [9] AMPK activators [10] AROCLOR1260 [11] ARSENIC TRIOXIDE [12-14] ARTEMISIN [15, 16] ASTAXANTHIN [17] ATORVASTATIN [18-21] AVISIMIBE [22] BDE-99, BDE-209 (polybrominated diphenyl ethers) [23] BERGAMOTTIN [24] BENZO[k]FLUOROANTHRENE [25]

2B6, 2C8, 2C9, 3A4

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3A4 1A 1A2, 3A4 2B6, 2C9, 3A4/5 3A4 1A1, 1A2 2B6, 3A4 2B6 2B6 1A1, 3A4 2B6, 3A4 2B6, 3A4 2B6, 2C9, 3A4 3A4 1A2, 3A4 1A1, 1A2, 2B6, 3A4 1A1, 1A2


BENZIMIDAZOLE-5-YLBENZENESULFONAMIDES [26] BIOCHANIN A [27] BISPHENOL A [28] BUTYLHYDROXYTOLUENE [29] BYAKANGELICIN [30] CAMPTOTHECIN [31] CARBAMAZEPINE [32] CARBOXYMEFLOQUINE [33] CARNOSIC ACID [34] CATECHOLAMINES [35] CHLORPYRIFOS [36] CITCO [37, 38] CLEVIDIPINE [39] CLINDAMYCIN [40] CLOFIBRATE [41] CLOTRIMAZOLE [32] COLCHICINE [42-44] CORTISOL [45] CRIZOTINIB [46] CYANIDIN [47] CYCLOPHOSPHAMIDE [48, 49] CYTOKINES / GROWTH FACTORS [45, 50-59] DABRAFENIB [60] DEXAMETHASONE [32, 38, 61-72] DICLOXACILLIN [40] 16

2B6, 3A4 2A6, 2B6, 2C9 1A1, 3A4 2B6, 3A4 3A4 3A4 2B6, 3A4 2B6, 2C8, 3A4 2B6, 3A4 3A4 1A1, 1A2, 2A6, 2B6, 3A4 2B6, 2C8 3A4 3A4 2C8, 3A4 2B6, 3A4 1A1, 1A2, 2B6, 2C8, 2C9, 3A4 3A4 3A4 1A1, 1A2 2B6, 3A4 1A1/2, 2B6, 2A6, 2C8/9, 2E1, 3A4 2B6, 3A4 1A1, 2A6, 2B6, 2C8/9, 3A4, 3A5 3A4


DIETHYLTOLUAMIDE [36] DIHYDROEPIANDROSTENON [72-74] DIINDOYLMETHANE [75-77] EMD 392949 (antidiabetic) [78] EFAVIRENZ [79] (-)-epigallocatechin gallate [80] ENDOSULFAN [81] ENTHOTELIN-A ANTAGON.(CI-1034) [82] EQUOL [83] ESTRADIOL [84-86] ETHANOL [87] ETRAVIRINE [88] FENOFIBRATE [41] FIPRONIL [89] FLUCLOXACILLIN [90] FLUVASTATIN [18] GEMFIBROSIL [41] GENTIOPICROSIDE [91] GINKGOLIDE A, B [92] GUGGULSTERONE [93] GW3965 (LXRα agonist) [94] HONOKIOL [95] HYPERFORIN [96-98] IBROLIPIM (NO-1886) [99, 100] IFOSFAMIDE [49]

1A1, 1A2, 2A6, 2B6, 3A4 1A1, 1A2, 2B6, 2C9 1A1, 1A2, 3A4 2C8, 3A4 3A4 1A1 2B6, 3A4 3A4 3A4 2A6, 2B6, 3A4 2E1, 3A4 3A4 2C8, 3A4 1A1, 2B6, 3A4 3A4 2B6, 3A4 2C8, 3A4 1A2, 3A4 3A4 3A4 3A4 2B6 2C9, 3A4 2C8, 3A4 2B6, 3A4

17


IRINOTECAN [31] ISOPENTANOL [87] ISRADIPINE [101] KETOCONAZOLE [102, 103] KHELLIN [104] KYNURENIC ACID [105] LANSOPRAZOLE [106-109] LCL161 (inhibitor of apoptosis proteins) [110] LIPOPOLYSACCHARIDE [35] LK-935 (statin) [20] LOVASTATIN [18] LY2090314 (GSK3 inhibitor) [111] MATRINE [112] MEDAZEPAM [113] MESALAZINE [114] METFORMIN [115-117] METHADONE [118, 119] METHANESULFONAMIDE C2BA-4 [120] METHOTREXATE [32] 4-METHYLBENZYLIDENE CAMPHOR [121] METOLACHLOR [7] METOLAZONE [122] METYRAPONE [123] MICONAZOLE [124] MIDAZOLAM [113]

3A4 2E1, 3A4 2B6, 2C9, 3A4 1A1, 1A2, 3A4 1A1 1A1, 1A2 1A1, 1A2, 1B1, 3A4 3A4 3A4 2B6, 2C9, 3A4 2B6, 3A4 CYP2B6 2A6, 2B6, 3A4 3A4 2B6, 3A4 2B6, 3A4 2B6, 3A4 2B6, 3A4 2B6, 3A4 2B6, 3A4 3A4 3A4 3A4 3A4 3A4

18


MIFEPRISTONE [125] ΜΚΧ−963(anti-aggregation platelet) [126] MOSAPRIDE [114] NAFCILLIN [40] β-NAPHTOFLAVONE [108] NELFINAVIR [127, 128] NICARDIPINE [101] NIFEDIPINE [101] NOCODAZOLE [44] NONYLPHENOL [129] OCHRATOXIN [130, 131] 4-tert-OCTYLPHENOL [121] OLTIPRAZ [132] OMEPRAZOLE [106-109, 133-135] ONCOSTATIN M [136] ORLISTAT [137] OXADIAZON [7] OXICONAZOLE [124] PANTOPRAZOLE [107] PARATHION [28] PELARGONIDIN [47] PENTACHLORODIBENZOFURAN [138] PERAZINE [139] PHENOBARBITAL [10, 32, 67, 68, 98, 134, 140-144] PHENYTOIN [32, 134, 145, 146]

3A4 3A4 1A2, 2B6, 3A4 3A4 1A1, 1A2, 1B1 2B6, 2C8, 2C9, 3A4 2B6, 2C9, 3A4 2B6, 2C9, 3A4 1A2 2B6 3A4 2B6, 3A4 2B6 1A1, 1A2, 1B1, 3A4 1A1, 1A2, 2B6, 2A6, 3A4 3A4 3A4 3A4 1A1, 3A4 1A1, 3A4 1A1, 1A2 1A1, 1A2 1A2, 2C19, 3A4 2A6, 2B6, 2C8, 2C9, 2C19, 3A4 2B6, 2C9, 3A4

19


Ph-morpholino-antioligomers [147] PHTALATES (DEHP, MEHP) [121, 148, 149] PIPERINE [150] PRETILACHLOR [7] PRIMAQUINE [108, 151] PROBENICID [32] PROGESTERONE [85] PROMAZINE [139] PROTOPINE [8] PYRAZOLE [152] PYRETHRINS [153] PYRETHROIDS [154-156] QUERCETIN [134] All-trans-RETINOIC ACID [157] RIFABUTIN [158-160] RIFAMPICIN [32, 40, 67, 69, 97, 98, 134, 141, 144, 158-162] RIFAPENTINE [158, 160] RITONAVIR [32, 127, 128] Ro 48-8071 (inh. 2,3-oxiskvalene:lanosterol cyclase) [163] ROSUVASTATIN [20] S16020 (anticancer) [164] SEMAGACESTAT (γ-secretase inhibitor) [165] SIMVASTATIN [18] SIPI5357 (antidepressant) [166] SP600125 (JNK inhibitor) [167] 20

3A4 2B6, 3A4 3A4 3A4 1A1, 1A2, 1B1 2B6, 3A4 2A6, 2B6, 2C8, 3A4, 3A5 1A2, 2C19, 3A4 1A1, 1A2 2A6 2B6, 3A4 1A1, 2A6, 2B6, 3A4 3A4 2C9 3A4 2A6, 2B6, 2C8/9, 2C19, 3A4, 3A7 3A4 2B6, 2C8, 2C9, 3A4 2B6, 3A4 2B6, 2C9, 3A4 1A1, 1A2 CYP3A4 2B6, 3A4 2B6 1A1, 1A2


SULFADIMINE [32] SULFINPYRAZONE [32] SULFISOXAZOLE [40] SULFORAPHANE [168, 169] T0901317 (LXR agonist) [170] TACE/MMP-inhibitors [171] TADALAFIL [172] TAMOXIFEN [173, 174] TAXOL [44, 175, 176] TETRACHLORODIBENZOFURAN [138] TETRACYCLINE [40] TCDD [138, 177-180] THALIDOMIDE [181] THIABENDAZOLE [29] α-TOCOPHEROL [182] TOPIRAMATE [183] TOREMIFENE [184] TROLEANDOMYCIN [32, 40, 185] TROGLITAZONE [186, 187] TSU-68 (anticancer) [188] U0126 (MEK1/2 inhibitor) [189] VALPROATE [190] VINBLASTINE [44] VINCRISTINE [44] VISNAGIN [104]

2B6, 3A4 2B6, 3A4 3A4 2A6, 3A4 2B6, 3A4 3A4 3A4 3A4 1A2, 3A4 1A1, 1A2 3A4 1A1, 1A2, 1B1 2B6, 3A4 1A2, 2B6, 3A4 3A4 3A4 3A4 2B6, 3A4 2B6, 3A4 1A1, 1A2 3A4 3A4 1A2 1A2 1A1

21


WARFARIN [191] WY14643 (PPARα agonist) [192, 193] YM758 (If channel inhibitor) [194]

2C9, 3A4 3A4 3A4

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Evaluation of 23 lots of commercially available cryopreserved hepatocytes for induction assays of human cytochromes P450.

Metabolism of palmatine by human hepatocytes and recombinant cytochromes P450.

Induction protocols for cytochromes P450IIIA in vivo and in primary cultures of animal and human hepatocytes.

Immunoisolation of human microsomal cytochromes P450 using autoantibodies.

Human hepatocytes in genotoxicity assays.

Constitutive expression and hormonal regulation of male sexually differentiated cytochromes P450 in primary cultured rat hepatocytes.

The human hepatic cytochromes P450 involved in drug metabolism.

Small intestinal cytochromes P450.

Challenges and Opportunities of Cytochrome P450-Mediated Phytoremediation.

Bacterial cytochromes P450: isolation and identification.

Identification and localization of cytochromes P450 in gut.

Role of cytochromes P450 in drug metabolism and hepatotoxicity.

The role of individual human cytochromes P450 in drug metabolism and clinical response.

4-hydroxylations of estradiol in human liver microsomes.

Interspecies features of hepatic cytochromes P450 IA1 and P450 IA2 in rodents.

Peroxygenase reactions catalyzed by cytochromes P450.

Membrane topology of the mammalian P450 cytochromes.

Azidowarfarin as photoaffinity probe of cytochromes P450.

Expression of two cytochromes P450 involved in carcinogen activation in a human colon cell line.

Caffeine as a probe for human cytochromes P450: validation using cDNA-expression, immunoinhibition and microsomal kinetic and inhibitor techniques.

Glucocorticoid-mediated potentiation of P450 induction in primary culture of rainbow trout hepatocytes.

Two cytochromes P450 catalyze S-heterocyclizations in cabbage phytoalexin biosynthesis.

Detection of human lung cytochromes P450 that are immunochemically related to cytochrome P450IIE1 and cytochrome P450IIIA.

P450 phosphorylation in isolated hepatocytes and in vivo.