Pesticide Biochemistry and Physiology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Pesticide Biochemistry and Physiology journal homepage: www.elsevier.com/locate/pest

Review

Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity Anshoo Malhotra a, D.K. Dhawan b,⇑ a b

Department of Biophysics, Post Graduate Institute of Medical Education & Research, Chandigarh, India Department of Biophysics, Panjab University, Chandigarh, India

a r t i c l e

i n f o

Article history: Received 10 October 2013 Accepted 21 April 2014 Available online xxxx Keywords: Zinc Hepatoprotection Pesticide toxicity

a b s t r a c t Human population bears the brunt of deadly hepatotoxic, neurodegenerative, behavioural and various other developmental disorders due to pesticide toxicity through environmental or occupational exposures. The application of pesticides to control pests in land and water has posed potential health hazards to live stock and wildlife including fishes, mammals, birds and humans. Therefore, various scientific approaches are being considered to tackle the problem of pesticide poisoning especially in developing economies. The role of essential trace elements as the promising and efficient preventive prophylactic agents without any toxicity and side effects in attenuating the adverse effects caused by pesticides, have been reported by various scientists, the world over. In this perspective, zinc, a key constituent of more than 300 mammalian enzymes and many transcription factors has proved its protective potential in various models of animal toxicity. The hepato-protective potential of zinc has been proved during various toxic states including pesticide toxicity. However, zinc warrants further examination with regard to documentation of specific molecular pathways to establish the exact mechanisms for zinc-mediated protection during pesticide toxicity. Ó 2014 Elsevier Inc. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Chlorpyrifos toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zinc – an overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zinc as an antioxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zinc: multiple roles in physiology. . . . . . . . . . . . . . . . . . . . . . . Zinc as a hepato-protector during pesticide induced toxicity . Zinc as a regulator of carbohydrate metabolism . . . . . . . . . . . Zinc as a regulator of drug metabolizing enzymes in liver . . . Zinc protective effects on microsomal APD activity. . . . . . . . . Zinc: future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

1. Chlorpyrifos toxicity Amongst many xenobiotics, pesticides on account of their high toxicity and selectivity cause a great concern to human health. Being wide spread environmental contaminants; the anticholines⇑ Corresponding author. Address: Department of Biophysics, Panjab University, Chanidgarh 160014, India. Mobile: +91 9878253746. E-mail address: [email protected] (D.K. Dhawan).

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

00 00 00 00 00 00 00 00 00 00

terase [antiChE] inhibitors compounds are probably the most manmade toxic chemicals. Human population at large is getting constantly exposed to pesticides through food stuffs and drinking water as the pesticides are used to enhance food production in agriculture sector. These compounds get absorbed rapidly by almost all the routes viz. dermal, respiratory, gastrointestinal, are highly lipid soluble and are classified as direct or indirect acetylcholinesterase inhibitors. Pesticides are metabolized primarily by hepatic cytochrome p450 enzymes which further activate indirect

http://dx.doi.org/10.1016/j.pestbp.2014.04.007 0048-3575/Ó 2014 Elsevier Inc. All rights reserved.

Please cite this article in press as: A. Malhotra, D.K. Dhawan, Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity, Pestic. Biochem. Physiol. (2014), http://dx.doi.org/10.1016/j.pestbp.2014.04.007

2

A. Malhotra, D.K. Dhawan / Pesticide Biochemistry and Physiology xxx (2014) xxx–xxx

Table 1 Chlorpyrifos toxicity studies. Sr. No.

Lead author and year

Chlorpyrifos toxic effect

Molecule/organ/system affected

1

Inhibition of antichloinesterase

2 3 4 5

Akhtar et al. (2009) [16]; Ajiboye et al. (2010) [60]; Ouyang et al. (2010) [61] Goel et al. (2007) [11] Goel et al. (2006) [14] Goel et al. (2006) [12] Goel et al. (2005) [78]

Brain, liver, kidney, spleen Liver Blood Liver Liver, blood

6 7 8 9 10 11 12

Malhotra et al. (2011) [15] Dow et al. (2002) [3] Wellman and Kramer (2004) [5] Long et al. (1986) [4] Cui et al. (2006) [6] Tian and Yamauchi (2003) [7]; Tian et al. (2007) [10] Yano et al. (2000) [8]; Lee et al. (2007) [9]

Cytochrome p450 (drug metablozing enzyme activity) Haematological indices changes, histoarchitecture of RBCs Alterations in carbohydrate metabolizing enzymes Changes in activities of antioxidant defence system enzymes, Hepatic histoarchitecture Neurotoxic effects, Behaviour changes Changes in body weight Diarrhoea due to chlolinergic over stimulation Breathing problems due to morphological changes in lungs Generation of reactive oxygen species Micronucleus formation Carcinogenesis

forms of organic phosphorous compounds [1,57,58]. It has been shown that repeated doses of chlorpyrifos were able to cause significant hepatic atrophy [2]. A number of studies have shown that exposure of pesticides in rats caused a significant inhibition of AChE activity in different tissues viz., liver, kidney and spleen [2,59–61]. Also, pesticide exposure generates oxidative stress in the body, as evidenced by increase in thiobarbituric acid reactive substances [TBARS], decrease in the levels of superoxide scavenging enzymes viz., superoxide dismutase [SOD], catalase [CAT] and glutathione peroxidase [GPx] in liver, kidney and spleen[3,62]. Pesticides have been reported to cause ill effects at almost all physiological levels/systems of the mammalian system. Chlorpyrifos resulted in decrease in the body weights of animal subjects upon different time exposures [3]. In respiratory systems, scientific reports have confirmed morphological changes in lungs leading to deaths of rats exposed to chlorpyrifos [4]. Gastrointestinal effects of chlropyrifos caused diarrhoea due to chlolinergic over stimulation [5]. Recent studies on chlorpyrifos demonstrated direct damage to DNA due to induction of reactive oxygen species [6]. Tian and Yamauchi observed micronucleus in 3-day mouse blastocysts following chlorpyrifos maternal exposure [7]. Some studies also addressed the potential carcinogenicity of chlorpyrifos [8,9]. Further, Tian et al. observed the similar results with confirming mitotic catastrophe upon chlorpyrifos exposure [10]. Earlier studies from our laboratory are in sync with above reports as we also observed toxic effects of chlorpyrifos on antioxidant defence enzymes, carbohydrate metabolizing enzymes, drug metabolizing enzymes and histoarchitecture in liver [11–13]. Chlorpyrifos significantly altered ultra-histoarchitecture of red blood cells along with changes in haematological indices [14]. A recent report from our lab also confirmed neurotoxic effects of chlorpyrifos in rat brain [15]. So, the above literature (Table 1) shows wide extent of toxicity caused by chlorpyrifos exposure. However, the present review shall mainly focus on the hepatic toxic effects of chlorpyrifos. 2. Zinc – an overview Zinc is an essential trace element and is required by all the living organisms because of its critical roles both as a structural component of proteins and as a cofactor in various enzymes mediated biochemical reactions [16]. The importance of zinc in human metabolism is illustrated by the deficiency of zinc which manifests itself in the form of effects which include a diminished immune response, reduced healing, hepatotoxicity and neurological disorders. Zinc has inimitable and broad role in physiological processes. Many biochemical roles of zinc have been reported since the

Brain Liver Gastrointestinal system Respiratory system DNA DNA Lung, brain, liver, stomach

discovery of this element as an essential nutrient for living organisms [17,18] which include roles in enzyme functions [19], nucleic acid metabolism [20,21], cell signaling [22] and apoptosis [23]. Further, the importance of zinc has been investigated in the physiological processes which include growth and development [24,25], lipid metabolism [26], brain and immune functions [27]. On the other hand, deficiency of zinc results in various pathological states. Basically, dietary factors are broadly responsible for zinc deficiency in addition to hereditary factors. However, the symptoms produced during zinc deficiency by either ways are almost similar. The initial effects of zinc deficiency include dermatitis, diarrhea, alopecia and loss of appetite [28,29]. More prolonged deficiency results in growth impairment and neuropsychological changes such as emotional instability, irritability and depression [30,31]. Many studies have reported that zinc deficiency causes decreased immune response which results in increased susceptibility to infections and that may lead to the death of patients [32–34]. The present review provides information on the protection afforded by zinc during hepatotoxicity created by chlorpyrifos pesticides and the molecular mechanisms involved to achieve such mitigating effects. 3. Zinc as an antioxidant An antioxidant can be defined as any substance that hinders a free radical reaction which involves oxygen. A free radical is any specie that contains one or more unpaired electrons. The antioxidant properties of zinc have been clearly demonstrated in various biochemical systems under different conditions of oxidative stress. The antioxidant mechanism of action of zinc can be broadly divided into two classifications namely chronic effects and acute effects. Chronic effects involve long term exposures of zinc to the subject under investigation which in turn results in the induction of some other substance to be an ultimate antioxidant. The induction of metallothionenis have been reported following chronic exposure to zinc. Metallothioneins are a group of low-molecularweight [6000–7000 kDa] metal-binding proteins containing 60– 68 amino acid residues, of which 25–30% are cysteine. They have the ability to bind 5–7 g zinc [mol/protein] [34–36]. Further, the chronic administration of zinc induces metallothionein under varied toxic states in different organs including brain [37,38], blood [39,40], intestine [41] and liver [42,43]. The second broad classification is acute effects of zinc treatment which further involves two sub-classifications namely protection of sulfhydryl groups and antagonism of the redox active transition metals. The first sub-classification is the mechanism which

Please cite this article in press as: A. Malhotra, D.K. Dhawan, Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity, Pestic. Biochem. Physiol. (2014), http://dx.doi.org/10.1016/j.pestbp.2014.04.007

A. Malhotra, D.K. Dhawan / Pesticide Biochemistry and Physiology xxx (2014) xxx–xxx

provides protection to sulfhydryl groups that in turn engrosses prevention of oxidation of these groups. One such enzyme which is reported in many studies is aminolevulinate dehydratase [ALAD] that catalyzes the formation of the pyrrole porphobilinogen from two molecules of d-aminolevulinic acid [44]. In humans, this enzyme exists as a homo-octamer of identical subunits, each with a molecular mass of 31,000–35,000 kDa [45]. d-Aminolevulinate dehydratase is sulfhydryl dependent, and there is a strong correlation between thiol oxidation state and enzyme activity [46,47]. Studies suggest that zinc is required for the active state of ALAD enzyme and has regulatory control over the enzyme [48,49]. In these ways, zinc helps this enzyme to attain optimum enzyme activity despite the toxic states. Zinc has been reported to maintain enzyme activity of ALAD during different toxic conditions in blood [50,51]. The possible justifications for the above protection afforded by zinc for ALAD is (a) the direct binding of zinc to sulfhydryl group, (b) the possible binding to some other protein site in close proximity to the sulfhydryl group which in turn leads to steric hindrance; (c) binding to some other site on the protein, resulting in a conformational change, with the net result of either of these processes being a reduction in the reactivity of sulfhydryl group I. Besides, there are various other enzymes like zinc finger proteins, primase, toposisomerases etc. containing similar groups where zinc has shown its protective effects [52–54]. The second sub classification of acute zinc protection mechanisms is antagonism of the redox transition elements like iron, copper which could be via competition of zinc with these elements for certain binding sites. The above competitive binding of zinc prevents free radical production in the biological systems [55,56].

3

homeostasis is well known [94]. In addition, zinc is also necessary to mobilize defense against reactive oxygen species [ROS] and H2O2-induced apoptosis [95]. 5. Zinc as a hepato-protector during pesticide induced toxicity Chlorpyrifos exposure have been observed to target glycolysis, glycogen synthesis, other cellular energy metabolism reactions and zinc has been reported to be protectively influence the same [96–99]. In this perspective, many studies reported various regulatory and protective functions of zinc on rat liver such as hepato-antioxidant [100], drug metabolizing enzyme regulator [101], carbohydrate metabolizing enzyme regulator and hepatocyte protector both at structural as well as ultra-structural level. The protective potential of zinc supplementation has been investigated in the liver of rats treated with chlorpyrifos [78] wherein zinc normalized the otherwise raised levels of lipid peroxidation to within normal limits. Lipid peroxidation is the process of oxidative degradation of polyunsaturated fatty acids [PUFA] and its occurrence in biological membranes causes impaired membrane function, structural integrity [102], decrease in membrane fluidity and inactivation of a several membrane bound enzymes. The normalization of LPO following zinc treatment is considered to be due to its antiperoxidative properties, as has been referred earlier. Zinc has also been reported to interact with cell membranes to stabilize them against various damaging effects, including those due to oxidative injuries. Further, chlorpyrifos-intoxicated animals when supplemented with zinc also showed a marked elevation in the hepatic MT pool, which is suggestive of its property to induce metallothionein synthesis.

4. Zinc: multiple roles in physiology 6. Zinc as a regulator of carbohydrate metabolism Zinc [Zn] is an essential trace element and is relatively nontoxic [63–66] and is required in many important functions in human metabolism [67–70]. Zinc is ubiquitous in sub-cellular metabolism and an essential component of catalytic site or sites of at least one enzyme in every enzyme classification [71,72]. Zinc is considered to be the second most important trace metal in the body after iron. It is known to be associated with metal binding proteins that regulate the functions of zinc as well copper [73]. Phosphotriesterases is one such class of metalloenzymes whose catalytic active centre includes two zinc cations and are involved in detoxification of broad range of toxic compounds including pesticides [74,75]. Further, being active catalytic centre of the enzyme phosphotriesterases, zinc also contributes towards its stability which has been proved by its comparative studies with other metal cations [76]. Zinc is present in the brain at high concentrations and regulates many physiological functions [77,78]. Zinc accumulates in some structures such as hippocampus or in selected neocortical layers or striatum [79]. About 10% of the total brain zinc is localized in glutamate containing synaptic vesicles, and is liberated during synaptic neurotransmitter release [80,81]. Following its release, zinc is reported to interact with many different membrane receptors and ion channels [82,83]. This divalent cation is an important molecule involved in neurotransmission [84,85]. Zinc stabilizes the cell membrane structure through its antioxidant actions by regulating the levels of metallothioneins and has also been reported to inhibit spontaneous lipid peroxidation in the rat brain [86]. It is a signaling messenger that is released by neural activity [87,88], and an essential catalytic or structural element of many proteins [89]. Concentrated in synaptic vesicles, zinc is released during neuronal activity. Extracellular zinc modulates the activity of ion channels such as the NMDA receptors [90], glycine receptors [91], GABA receptors [92], and store-operated Ca2+ channels [93]. Furthermore, the relevance of zinc in cognitive development and CNS

The chlorpyrifos treatment has been reported to cause alterations in the activities of carbohydrate metabolizing enzymes which are supposedly crucial in regulating the energy metabolism in response to increased ATP requirement of the body under toxic conditions [103]. A significant elevation of glycogen phosphorylase and depressed glycogen contents in liver have been observed following chlorpyrifos intoxication. Hepatic glyconeogenesis plays a pivotal role in the glucose homeostasis, which otherwise gets compromised due to excessive utilization during pesticide induced toxicity. It has also been suggested in some studies that in certain conditions, when blood glucose concentrations plummet significantly due to either lesser starch intake or some other reason, glycogen stored in the liver cells gets degraded to supply the required glucose levels in the body [104] Further, the enzyme activity of hexokinase showed significant inhibition following chlorpyrifos intoxication which is indicative of overall suppressed process of glycolysis. Depressed 14C-glucose uptake in animals treated with pesticides has also been seen in some studies [37]. Furthermore, depressed hexokinase activities would result in lack of conversion of excess glucose to glucose-6-phosphate. Also, a significant decrease in the uptake of 14C-glucose reflects the status of glycogen, in chlorpyrifos intoxicated animals and therefore, confirms the increased rate of glycogenolysis. Zinc when administered to chlorpyrifos-intoxicated animals the activities of glycogen phosphorylase and hexokinase activities were observed to be elevated [103,104]. Moreover, a recent report has also pointed out that MT-associated Zn, rather than increased intracellular Zn per se is involved in the regulation of hepatic carbohydrate metabolism [105]. It was commented that the extra zinc in a cell is associated with MT, suggesting that the increased glycolytic activity is a result of increase in pool of freely available zinc in the form of Zn-MT. Although, there are no reports in this context, but above studies

Please cite this article in press as: A. Malhotra, D.K. Dhawan, Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity, Pestic. Biochem. Physiol. (2014), http://dx.doi.org/10.1016/j.pestbp.2014.04.007

4

A. Malhotra, D.K. Dhawan / Pesticide Biochemistry and Physiology xxx (2014) xxx–xxx

provide some evidence to believe that zinc may be associated in the regulation of carbohydrate metabolism by increasing the rate of glycogenolysis and inhibiting the process of gluconeogenesis, which results in some sort of homeostatic regulation of liver glucose concentrations.

these protective effects of zinc needs to be explored. Therefore, further research is warranted to achieve a clear understanding with regard to role of zinc in providing protection during pesticide poisoning at the molecular level. References

7. Zinc as a regulator of drug metabolizing enzymes in liver Drug-metabolizing enzymes play a vital role in the bio-activation and metabolism of chlorpyrifos in the liver. Hepatic microsomal activities of most of the drug-metabolizing enzymes have been shown to be significantly depressed following chlorpyrifos intoxication, however, simultaneous zinc co-administration to these animals was able to restore these enzyme activities to within normal limits, suggesting its protective potential. Cytochrome P450 enzyme system plays an important role in the bio-activation of chlorpyrifos which is central to the toxic manifestation of OP insecticides. An overall significant inhibition in the activity of the microsomal cytochrome P450 and cytochrome b5 following chlorpyrifos intoxication has been observed in some studies [106]. Chorpyrifos has been shown to inhibit the activities of both NADPH cytochrome-c-reductase and NADH cytochrome-c-reductase. NADPH cytochrome-c-reductase, a flavoprotein present in endoplasmic reticulum is thought to be involved in the oxidation of various drugs, steroids and other chemicals [107]. NADPH cytochrome-c-reductase is involved in initiating the process of NADPHdependent lipid peroxidation in the microsomal membranes, and increased lipid-peroxidation as a result of chlorpyrifos intoxication may also be the cause of depressed enzymatic activity [108]. The observed decrease in the cytochrome b5 and subsequent concomitant decrease in NADH cytochrome-c-reductase with chlorpyrifos intoxication could also be explained on a similar basis, as cytochrome b5 potentiates the catalytic desaturation of fatty acids [109]. 8. Zinc protective effects on microsomal APD activity Microsomal APD activity also gets suppressed in chlorpyrifos intoxicated animals. It has been shown that zinc regulates the hepatic microsomal drug metabolism, as well as the related oxidation of NADPH in the setting of chlorpyrifos intoxication. Zinc activates microsomal pyrophosphatases II, a zinc containing enzyme that is capable of metabolizing both NADPH and NADH [110]. Zinc is known to complex with NADPH, and it is suggested that regulation of drug metabolism by zinc might be due to this complex formation [111]. It has also been hypothesized that zinc by binding to reductase, changes its oxidation–reduction potential, thus impacting the regulation of the cytochrome P450 levels [112]. Besides, it is known that majority of zinc in liver exists bound to zinc-metallothionein and this trace metal may be readily available to the hepatic cytochromes [113,114]. Also, it can been hypothesized that the increase in Zn turnover in concert with the synthesis of metallothionein [MT] might be pivotal behind these effects, however, further studies are still required in this context. It has been shown that liver microsomes from zinc deficient rats generate more NADPH and aminopyrene-dependent H2O2 due to simultaneously inhibited APD activity in these animals [115]. 9. Zinc: future prospects It becomes abundantly clear from literature that zinc is an extraordinary hepato-protector element and can be used as a prophylactic agent during pesticide toxicity. Zinc has shown its efficacy in ameliorating various hepatotoxic effects caused by chlorpyrifos. However, in depth mechanistic reasoning behind

[1] C.A. Ellison, Y. Tian, J.B. Knaak, P.J. Kostyniak, J.R. Olson, Human hepatic cytochrome P450-specific metabolism of the organophosphorus pesticides methyl parathion and diazinon, Drug Metab. Dispos. 40 (1) (2012) 1–5. [2] H. Xing, Z. Zhang, H. Yao, T. Liu, L. Wang, S. Xu, S. Li, Effects of atrazine and chlorpyrifos on cytochrome P450 in common carp liver, Chemosphere 104 (2014) 244–250. [3] Dow, Toxicology studies on metabolites; Chapter 5.8.1 In Toxicological and metabolism studies on the active substance, Dow Agrosciences, Midland, MI, 2002. [4] G.G. Long, A.B. Scheidt, R.J. Everson, F.W. Oehme, Age related susceptibility of newborn pigs to the cutaneous application of chlorpyrifos, Vet. Hum. Toxicol. 28 (1986) 297–299. [5] S.E. Wellman, R.E. Kramer, Absence of DNA binding activity of methyl parathion and chlorpyrifos, Toxicol. Mech. Methods 14 (2004) 247–251. [6] Y. Cui, J. Guo, B. Xu, Z. Chen, Potential of chlorpyrifos and cypermethrin forming DNA adducts, Mutat. Res. 604 (2006) 36–41. [7] Y. Tian, T. Yamauchi, Micronucleus formation in 3-day mouse embryos associated with maternal exposure to chlorpyrifos during the early preimplantation period, Reprod. Toxicol. 17 (2003) 401–405. [8] B.L. Yano, J.T. Young, J.L. Mattsson, Lack of carcinogenicity of chlorpyrifos insecticide in a high-dose, 2-year dietary toxicity study in Fischer 344 rats, Toxicol. Sci. 53 (2000) 135–144. [9] W.J. Lee, D.P. Sandler, A. Blair, C. Samanic, A.J. Cross, M.C. Alavanja, Pesticide use and colorectal cancer risk in the agricultural health study, Int. J. Cancer 121 (2007) 339–346. [10] Y. Tian, L. Shen, Y. Gao, T. Yamauchi, X.-M. Shen, N. Ma, Comparison of 40 ,60 diamidino-2-phenylindole and Giemsa stainings in preimplantation mouse embryos micronucleus assay including a triple dose study, Ind. Health 45 (2007) 343–347. [11] A. Goel, V. Dani, D.K. Dhawan, Zinc mediates normalization of hepatic drug metabolizing enzymes in chlorpyrifos-induced toxicity, Toxicol. Lett. 169 (1) (2007) 26–33. [12] A. Goel, V. Dani, D.K. Dhawan, Chlorpyrifos-induced alterations in the activities of carbohydrate metabolizing enzymes in rat liver: the role of zinc, Toxicol. Lett. 163 (3) (2006) 235–241. [13] A. Goel, D.K. Dhawan, Zinc supplementation prevents liver injury in chlorpyrifos-treated rats, Biol. Trace Elem. Res. 82 (1–3) (2001) 185–200. [14] Ajay Goel, Vijayta Dani, D.K. Dhawan, Role of zinc in mitigating the toxic effects of chlorpyrifos on hematological alterations and electron microscopic observations in rat blood, Biometals 19 (2006) 483–492. [15] A. Malhotra, P. Nair, D.K. Dhawan, Efficacy of zinc as a nutritional supplement in ameliorating chlorpyrifos-induced neurotoxicity in rats, J. Environ. Pathol. Toxicol. Oncol. 30 (3) (2011) 225–233. [16] M.L. Ackland, Michalczk, Zinc deficiency and its inherited disorders – a review, Gene Nutr. 1 (2006) 41–50. [17] J. Raulin, Etudes clinique sur la vegetation. Annales des Science as Naturelle, Botanique 11 (1869) 93–299. [18] P. Maze, Influences respectives des elements de la solution mineral du mais, Annales de l’Institut Pasteur (Paris) 28 (1914) 21–69. [19] B.L. Vallee, D.S. Auld, Zinc coordination, function, and structure of zinc enzymes and other proteins, Biochemistry 29 (1990) 5647–5659. [20] W.J. Miller, D.M. Blackmon, R.P. Gentry, W.J. Pitts, G.W. Powell, Absorption, excretion, and retention of orally administered zinc-65 in various tissues of zinc-deficient and normal goats and calves, J. Nutr. 92 (1967) 71–78. [21] R.S. Brown, C. Sander, P. Argos, The primarynstructure of transcription factor IIIA has 12 consecutive repeats, FEBS Lett. 186 (1985) 271–274. [22] T.J. McNulty, C.W. Taylor, Extracellular heavymetal ions stimulate Ca2+ mobilization in hepatocytes, Biochem. J. 339 (Pt 3) (1999) 555–561. [23] P.D. Zalewski, I.J. Forbes, W.H. Betts, Correlation of apoptosis with change in intracellular labile Zn(II) using zinquin ((2-methyl-8-ptoluenesulphonamido-6-quinolyloxy)acetic acid), a new specific fluorescent probe for Zn(II), Biochem. J. 296 (1993) 403–408. [24] A.S. Prasad, Clinical manifestations of zinc deficiency, Annu. Rev. Nut. 5 (1985) 341–363. [25] A.S. Prasad, Role of zinc in human health, Bol. Asoc. Med. P. R. 83 (1991) 558– 560. [26] S.C. Cunnane, Role of zinc in lipid and fatty acid metabolism and in membranes, Prog. Food Nutr. Sci. 12 (1988) 151–188. [27] L. Endre, Z. Katona, K. Gyurkovits, Zinc deficiency and cellular immune deficiency in acrodermatitis enteropathica, Lancet 2 (1975). 119-6. [28] P.J. Aggett, The assessment of zinc status: a personal view, Proc. Nutr. Soc. 1 (50) (1991) 9–17. [29] M.L. Ackland, D.M. Danks, H.J. McArdle, Zinc transport by fibroblasts from patients with acrodermatitis enteropathica, Biol. Trace Elem. Res. 22 (1989) 257–263. [30] J.A. Halsted, H.A. Ronaghy, P. Abadi, Zinc deficiency in man, Am. J. Med. 1972 (53) (1972) 277–284.

Please cite this article in press as: A. Malhotra, D.K. Dhawan, Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity, Pestic. Biochem. Physiol. (2014), http://dx.doi.org/10.1016/j.pestbp.2014.04.007

A. Malhotra, D.K. Dhawan / Pesticide Biochemistry and Physiology xxx (2014) xxx–xxx [31] A.E. Rodin, A.S. Goldman, Autopsy findings in acrodermatitis enteropathica, Am. J. Clin. Pathol. 51 (1969) 315–322. [32] R. Julius, M. Schulkind, T. Sprinkle, O. Rennert, Acrodermatitis enteropathica with immune deficiency, J. Pediatr. 83 (1973) (1973) 1007–1011. [33] R.S. Beach, M.E. Gershwin, R.K. Makishima, L.S. Hurley, Impaired immunologic ontogeny in postnatal zinc deprivation, J. Nutr. 110 (1980) 805–815. [34] W.R. Bernhard, M. Vasak, J.H. Kagi, Cadmium binding and metal cluster formation in metallothionein: a differential modification study, EXS 52 (52) (1987) 243–246. [35] J.H. Kagi, P. Hunziker, Mammalian metallothionein, Biol. Trace Elem. Res. 21 (1989) 111–118. [36] J.H. Kagi, Y. Kojima, Chemistry and biochemistry of metallothionein, EXS 52 (1987) 25–61. [37] P. Bhalla, V.D. Chadha, R. Dhar, D.K. Dhawan, Neuroprotective effects of zinc on antioxidant defense system in lithium treated rat brain, Indian J. Exp. Biol. 45 (11) (2007 Nov) 954–958. [38] A. Takeda, H. Tamano, Zinc signaling through glucocorticoid and glutamate signaling in stressful circumstances, J. Neurosci. Res. 14 (2010) 3002–3010. [39] A. Malhotra, D.K. Dhawan, Zinc improves antioxidative enzymes in red blood cells and hematology in lithium-treated rats, Nutr. Res. 28 (1) (2008) 43–50. [40] O. Fırat, F. Kargın, Effects of zinc and cadmium on erythrocyte antioxidant systems of a freshwater fish Oreochromis niloticus, J. Biochem. Mol. Toxicol. 4 (2010) 223–229. [41] V.D. Chadha, D.K. Dhawan, Membrane fluidity and surface changes during initiation of 1,2 dimethylhydrazine-induced colon carcinogenesis: protection by zinc, Oncol. Res. 18 (1) (2009) 17–23. [42] C. Saito, H.M. Yan, A. Artigues, M.T. Villar, A. Farhood, H. Jaeschke, Mechanism of protection by metallothionein against acetaminophen hepatotoxicity, Toxicol. Appl. Pharmacol. 242 (2) (2010) 182–190. [43] H. Jihen el, M. Imed, H. Fatima, K. Abdelhamid, Protective effects of selenium (Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver of the rat: effects on the oxidative stress, Ecotoxicol. Environ. Saf. 72 (5) (2009) 1559–1564. [44] J. Fujihara, T. Agusa, T. Yasuda, M. Soejima, H. Kato, A. Panduro, Y. Koda, K. Kimura-Kataoka, H. Takeshita, Ethnic variation in genotype frequencies of delta-aminolevulinic acid dehydratase (ALAD), Toxicol. Lett. 191 (2–3) (2009 Dec 15) 236–239. [45] P.M. Anderson, R.J. Desnick, Purification and properties of deltaaminolevulinate dehydratase from human erythrocytes, J. Biol. Chem. 254 (15) (1979) 6924–6930. [46] S.N. Kelada, E. Shelton, R.B. Kaufmann, M.J. Khoury, Delta-aminolevulinic acid dehydratase genotype and lead toxicity: a HuGE review, Am. J. Epidemiol. 154 (1) (2001) 1–13. [47] A. Bernard, R. Lauwerys, Metal-induced alterations of delta-aminolevulinic acid dehydratase, Ann. NY Acad. Sci. 514 (1987) 41–47. [48] T.J. Simons, The affinity of human erythrocyte porphobilinogen synthase for Zn2+ and Pb2+, Eur. J. Biochem. 234 (1995) 178–183. [49] P.N.B. Gibbs, M.G. Gore, P.M. Jordan, Investigation of the effect of metal ions on the reactivity of thiol groups in human d-aminolevulinate dehydratase, Biochem. J. 225 (1985) 573–580. [50] P.L. Goering, B.A. Fowler, Activation of delta-aminolevulinic acid dehydratase following donation of zinc from kidney metallothionein, EXS 52 (1987) 613– 616. [51] B. Haeger-Aronsen, A. Schütz, Antagonistic effect in vivo of zinc on inhibition of delta-aminolevulinic acid dehydratase by lead, Arch. Environ. Health 31 (4) (1976) 215–220. [52] T.M. Bray, W.J. Bettger, The physiologic role of zinc as an antioxidant, Free Radic. Biol. Med. 8 (1990) 281–291. [53] A. Klug, D. Rhodes, Zinc fingers: a novel protein motif for nucleic acid recognition, TIBS 7 (1998) 464–473. [54] M.A. Griep, E.R. Lokey, The role of zinc and the reactivity of cysteines in Escherichia coli primase, Biochemistry 35 (1996) 8260–8267. [55] E. Kara, M. Gunay, I. Cicioglu, M. Ozal, M. Kilic, R. Mogulkoc, A.K. Baltaci, Effect of zinc supplementation on antioxidant activity in young wrestlers, Biol. Trace Elem. Res. 134 (1) (2010) 55–63. Epub 2009 Jul 14. [56] A. Szuster-Ciesielska, A. Stachura, M. Słotwin´ska, T. Kamin´ska, R. Sniezko, R. Paduch, D. Abramczyk, J. Filar, M. Kandefer-Szerszen´, The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive oxygen species (ROS) production in cell cultures, Toxicology 145 (2–3) (2000) 159–171. [57] E. Hodgson, R.L. Rose, Human metabolic interactions of environmental chemicals, J. Biochem. Mol. Toxicol. 21 (4) (2007) 182–186. [58] Robert J. Foxenberg, Barbara P. McGarrigle, James B. Knaak, Paul J. Kostyniak, James R. Olson, Human hepatic cytochrome P450-specific metabolism of parathion and chlorpyrifos, Drug Metab. Dispos. 35 (2) (2007) 189–193. [59] N. Akhtar, M.K. Srivastava, R.B. Raizada, Assessment of chlorpyrifos toxicity on certain organs in rat, Rattus norvegicus, J. Environ. Biol. 30 (6) (2009) 1047– 1053. [60] T.O. Ajiboye, Redox status of the liver and kidney of 2,2-dichlorovinyl dimethyl phosphate (DDVP) treated rats, Chem. Biol. Interact. 185 (3) (2010 May 14) 202–207. Epub 2010 Mar 17. [61] Y.H. Ouyang, S.L. Li, W. Song, N. Zhao, Z.F. Ma, Effect of penehyclidine hydrochloride on tumor necrosis factor-alpha in liver and spleen in mice with acute organophosphorus pesticide poisoning, Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 22 (4) (2010) 238–239.

5

[62] A. Slaninova, M. Smutna, H. Modra, Z. Svobodova, A review: oxidative stress in fish induced by pesticides, Neuro. Endocrinol. Lett. 30 (Suppl. 1) (2009) 2– 12. [63] S. Joshi, S.K. Hasan, R. Chandra, M.M. Hussain, R.C. Shrivastava, Scavenging action of zinc and green tea polyphenol on cisplatin and nickel induced ntric oxide generation and lipid peroxidation in rats, Biomed. Environ. Sci. 17 (2004) 402–409. [64] Z. Zhou, L. Wang, Z. Song, J.T. Saari, C.J. McClain, Y.J. Kang, Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress, Am. J. Pathol. 166 (6) (2005) 1681–1690. [65] R.L. Betholf, Zinc, in: H.G. Seiler (Ed.), Handbook Toxicology of Inorganic Compounds, Siegel Dekker, New York, 1988, p. 788. [66] K. Jeejeebhoy, Zinc: an essential trace element for parenteral nutrition, Gastroenterology 137 (5 Suppl.) (2009) S7–S12. [67] A.S. Prasad, Clinical, biochemical and nutritional spectrum of zinc deficiency in human subjects: an update, Nutr. Rev. 41 (1983) 197–208. [68] Erik G. Brandt, Mikko Hellgren, Tore Brinck, Tomas Bergman, Olle Edholm, Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site, Phys. Chem. Chem. Phys. 11 (6) (2009) 975–983. [69] L. Rink, P. Gabriel, Zinc and the immune system, Proc. Nutr. Soc. 59 (2000) 541. [70] Raul A. Wapnir, Protein Nutrition and Mineral Absorption, CRC Press, Boca Raton, Florida, 1990. [71] K.A. McCall, C. Huang, C.A. Fierke, Function and mechanism of zinc metalloenzymes, J. Nutr. 130 (2000). 1437S-46S. [72] P. Coyle, J.C. Philcox, L.C. Carey, A.M. Rofe, Metallothionein: the multipurpose protein, Cell. Mol. Life Sci. 59 (2002) 627–647. [73] B.L. Vallee, K.H. Falchuk, The biochemical basis of zinc physiol, Physiol. Rev. 73 (1) (1993) 79–118. [74] F.M. Raushel, Bacterial detoxification of organophosphate nerve agents, Curr. Opin. Microbiol. 5 (2002) 288–296. [75] D.P. Dumas, H.D. Durst, W.G. Landis, F.M. Raushel, Inactivation of organophosphorus nerve agents by the phosphotriesterase from Pseudomonas diminuta, Arch. Biochem. Biophys. 277 (1990) 155–159. [76] R.O.C.H.U. Daniel, Nathalie VIGUI´E, Fr´ed´erique RENAULT, David CROUZIER, Marie-Th´er‘ese FROMENT and Patrick MASSON. Contribution of the activesite metal cation to the catalytic activity and to the conformational stability of phosphotriesterase: temperature- and pH-dependence, Biochem. J. 380 (2004) 627–633. [77] B. Singh, D. Dhawan, B. Chand, P.C. Mangal, P.N. Trehen, Trace element distribution in rat brain following lead and lithium supplementation-a study using an EDXRF spectrometer, Appl. Radiat. Isol. 46 (1) (1995) 59–64. [78] Ajay Goel, Vijayta Dani, D.K. Dhawan, Protective effects of zinc on lipid peroxidation, antioxidant enzymes and hepatic histoarchitecture in chlorpyrifos-induced toxicity, Chem. Biol. Interact. (2005) 131–140. [79] C.J. Frederickson, Importance of zinc in the central nervous system, J. Nutr. (2000) 130–147. [80] P.M. Filipe, A.C. Fernandes, C.F. Manso, Effect of zinc on copper-induced and spontaneous lipid peroxidation, Biol. Trace Elem. Res. 117 (1995) 51–56. [81] B.K. Bitanihirwe, M.G. Cunningham, Zinc: the brain’s dark horse, Synapse 63 (2009) 1029. [82] N.L. Harrison, S.J. Gibbson, Zn21: an endogenous modulator of ligand- and voltage-gated ion channels, Neuropharmacology 33 (1994) 935–952. [83] A.S. Nakashima, R.H. Dyck, Zinc and cortical plasticity, Brain Res. Rev. 59 (2009) 347. [84] D.E. Baranano, C.D. Ferris, S.H. Snyder, Atypical neural messengers, Trends Neurosci. 24 (2001) 99–106. [85] T.G. Smart, A.M. Hosie, P.S. Miller, Zn2+ ions: modulators of excitatory and inhibitory synaptic activity, Neuroscience 10 (2004) 432–442. [86] S.R. Powell, The antioxidant properties of zinc, J. Nutr. 130 (2000) S1447– S1545. [87] W. Kresse, I. Sekler, A. Hoffmann, O. Peters, C. Nolte, A. Moran, H. Kettenmann, Zinc ions are endogenous modulators of neurotrasmitter- stimulated capacitative Ca2+ entry in both cultured and in situ mouse astrocytes, Eur. J. Neurosci. 21 (2005) 1626–1634. [88] Michal Hershfinkel, William F. Silverman, Israel Sekler, The zinc sensing receptor a link between zinc and cell signaling, Mol. Med. 13 (2007) 331. [89] D.W. Choi, J.Y. Koh, Zinc and brain injury, Annu. Rev. Neurosci. 121 (1998) 347–375. [90] Y. Choi, H.V. Chen, S.A. Lipton, Three pairs of cysteine residues mediate both redox and Zn2+ modulation of the nmda receptor, J. Neurosci. 2001 (21) (2001) 392–400. [91] R.J. Harvey, P. Thomas, C.H. James, A. Wilderspin, T.G. Smart, Identification of an in- hibitory Zn2+ binding site on the human glycine receptor alpha1 subunit, J. Physiol. 520 (1999) 53–64. [92] X. Xie, R.C. Hider, T.G. Smart, Modulation of GABA-mediated synaptic transmission by endogenous zinc in the immature rat hippocampus in vitro, J. Physiol. 478 (1994) 75–86. [93] C.R. Jan, S.N. Wu, C.J. Tseng, Zn2+ increases resting cytosolic Ca2+ levels and abolishes capacitative Ca2+ entry induced by ATP in MDCK cells, Naunyn Schmiedebergs Arch. Pharmacol. 360 (1999) 249–255. [94] A. Takeda, A. Minami, S. Takefuta, M. Tochigi, N. Oku, Zinc homeostasis in the brain of adult rats fed zinc-deficient diet, J. Neurosci. Res. 63 (2001) 447–452.

Please cite this article in press as: A. Malhotra, D.K. Dhawan, Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity, Pestic. Biochem. Physiol. (2014), http://dx.doi.org/10.1016/j.pestbp.2014.04.007

6

A. Malhotra, D.K. Dhawan / Pesticide Biochemistry and Physiology xxx (2014) xxx–xxx

[95] M.J. Chung, P.A. Walker, R.W. Brown, C. Hogstrand, Zinc-mediated gene expression offers protection against H2 O2 -induced cytotoxicity, Toxicol. Appl. Pharmacol. 205 (2005) 225–236. [96] J.E. Coleman, Zinc proteins: enzymes, storage proteins, transcription factors and replication proteins, Ann. Rev. Biochem. 61 (1992) 897–946. [97] O.M. Steinebach, H.T. Wolterbeek, Effects of zinc on rat hepatoma HTC cells and primary cultured rat hepatocytes, Toxicol. Appl. Pharmacol. 118 (1993) 245–254. [98] N. Tamaki, T. Ikeda, A. Funatsuka, Zinc as activating cation for muscle glycolysis, J. Nutr. Sci. Vitaminol. (Tokyo) 29 (1983) 655–662. [99] A.M. Rofe, J.C. Philcox, P. Coyle, Activation of glycolysis by zinc is diminished in hepatocytes from metallothionein-null mice, Biol. Trace Elem. Res. 75 (2000) 87–97. [100] V. Kesik, M.K. Lenk, A.E. Kurekci, C.H. Acikel, E.O. Akgul, A. Aydin, O. Erdem, M. Gamsizkan, Do zinc and selenium prevent the antioxidant, hepatic and renal system impairment caused by aspirin in rats?, Biol Trace Elem. Res. 23 (1–3) (2008) 168–178. [101] M. Cabré, J. Camps, N. Ferré, J.L. Paternáin, J. Joven, The antioxidant and hepatoprotective effects of zinc are related to hepatic cytochrome P450 depression and metallothionein induction in rats with experimental cirrhosis, Int. J. Vitam. Nutr. Res. 71 (4) (2001 Jul) 229–236. [102] J.M. Gutteridge, B. Halliwell, Free radicals and antioxidants in the year 2000: a 404 historical look to the future, Ann. NY Acad. Sci. 899 (2000) 136–147. [103] A. Goel, D.P. Chauhan, D.K. Dhawan, Protective effects of zinc in chlorpyrifos induced hepatotoxicity: a biochemical and trace elemental study, Biol. Trace Elem. Res. 74 (2) (2000) 171–183. [104] F.C. Kauffman, L.H. Davis, M. Whittaker, Activation of glycogen phosphorylase in rat pheochromocytoma PC12 cells and isolated hepatocytes by organophosphates, Biochem. Pharmacol. 39 (1990) 347–354. [105] A.M. Rofe, J.C. Philcox, P. Coyle, Activation of glycolysis by zinc is diminished in hepatocytes from metallothionein-null mice, Biol. Trace Elem. Res. 75 (2000) 87–97.

[106] L.G. Sultatos, S.D. Murphy, Hepatic microsomal detoxification of the organophosphates paraoxon and chlorpyrifos oxon in the mouse, Drug Metab. Dispos. 111 (3) (1983) 232–238. [107] B.S. Masters, The journey from NADPH-cytochrome P450 oxidoreductase to nitric oxide synthases, Biochem. Biophys. Res. Commun. 338 (1) (2005) 507– 519. [108] A. Sevanian, K. Nordenbrand, E. Kim, L. Ernster, et al., Microsomal lipid peroxidation: the role of NADPH–cytochrome P450 reductase and cytochrome P450, Free Radic. Biol. Med. 8 (2) (1990) 145–152. [109] A. Hildebrandt, R.W. Estabrook, Evidence for the participation of cytochrome b 5 in hepatic microsomal mixed-function oxidation reactions, Arch. Biochem. Biophys. 143 (1) (1971) 66–79. [110] A.B. Zyryanov, M. Tammenkoski, A. Salminen, G.Y. Kolomiytseva, I.P. Fabrichniy, A. Goldman, R. Lahti, A.A. Baykov, Site-specific effects of zinc on the activity of family II pyrophophatase, Biochemistry 43 (45) (2004) 14395– 14402. [111] J.C. Ludwig, R.L. Misiorowski, M. Chvapil, M.D. Seymour, Interaction of zinc ions with electron carrying coenzymes NADPH and NADH, Chem. Biol. Interact. 30 (1) (1980) 25–34. [112] Z. Zhou, L. Wang, Z. Song, J.T. Saari, C.J. McClain, Y.J. Kang, Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress, Am. J. Pathol. 166 (6) (2005) 1681–1690. [113] I. Bremner, N.T. Davies, The induction of metallothionein in rat liver by zinc injection and restriction of food intake, Biochem. J. 149 (3) (1975) 733–738. [114] D.L. Eaton, N.H. Stacey, K.L. Wong, C.D. Klaassen, Dose-response effects of various metal ions on rat liver metallothionein, glutathione, heme oxygenase, and cytochrome P-450, Toxicol. Appl. Pharmacol. 55 (2) (1980) 393–402. [115] J.D. Hammermueller, T.M. Bray, W.J. Bettger, Effect of zinc and copper deficiency on microsomal NADPH-dependent active oxygen generation in rat lung and liver, J. Nutr. 117 (5) (1987) 894–901.

Please cite this article in press as: A. Malhotra, D.K. Dhawan, Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity, Pestic. Biochem. Physiol. (2014), http://dx.doi.org/10.1016/j.pestbp.2014.04.007