Cisplatin-Induced Hepatotoxicity Is Enhanced by Elevated Expression of Cytochrome P450 2E1

The Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Toxicological Sciences (Impact Factor: 3.85). 03/2006; 89(2):515-23. DOI: 10.1093/toxsci/kfj031
Source: PubMed


In this study, the possible potentiation of cisplatin-induced hepatotoxicity by cytochrome P450 2E1 (CYP2E1) was examined both in vitro and in vivo. Transfected HepG2 cells expressing CYP2E1 (E47 cells) and not expressing CYP2E1 (C34 cells) were used as an in vitro model, and mice drinking 2% acetone for 7 days to induce CYP2E1 were used as an in vivo model. Exposure of E47 cells to cisplatin caused a much greater loss of cell viability, more striking depletion of reduced glutathione (GSH), and higher reactive oxygen species (ROS) production as compared with C34 cells. The prooxidant L-buthionine-[R,S]-sulfoximine (BSO), which depletes GSH, enhanced cisplatin-induced loss of cell viability, whereas the antioxidant glutathione ethyl ester, or the iron chelator deferoxamine mesylate (DFO) protected against the cisplatin-induced loss of E47 cell viability. Diallyl sulfide (DAS), an inhibitor of CYP2E1, also protected against the cisplatin toxicity in the E47 cells. After being injected with cisplatin (ip, 45 mg/kg), mice drinking 2% acetone with increased CYP2E1 levels exhibited elevated levels of serum ALT and AST, liver caspase-3 activity and positive staining of TUNEL increased, and histopathology indicated the presence of necrotic foci in livers of acetone plus cisplatin-treated mice. Lipid peroxidation and protein oxidation as indicated by carbonyl formation, staining of 3-nitrotyrosine (3-NT) and iron were higher in the cisplatin plus acetone group, compared with cisplatin alone group. Both in vitro and in vivo results indicate that elevated CYP2E1 enhances cisplatin-induced hepatotoxicity, and the mechanism may involve increased production of ROS and oxidative stress.

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    • "Unfortunately, therapeutic potential of these drugs is limited by its ototoxicity, neurotoxicity, nephrotoxicity, and hepatotoxicity (Church et al., 2004; Steeg and Theodorescu, 2008; Ciftci et al., 2011). Earlier, it has been reported that simultaneous administration of some antiemetic drugs exaggerated the hepatic toxicity induced by cisplatin (Lu and Cederbaum, 2006). Thus ameliorating chemotherapeutic drug(s) toxicity on non-target tissues is an important health-related goal. "
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    ABSTRACT: This study was undertaken to investigate whether administration of melatonin protects PVB-Induced oxidative and metabolic toxicity in the liver of Wistar rats. Adult male Wistar rats were intraperitoneally injected with either melatonin or PVB (cisplatin, vinblastine, and bleomycin) alone or combination for a period of 9 weeks. A significant increase in lipid peroxidation levels and decrease in catalase and superoxide dismutase activity levels were observed in the liver mitochondria of rats treated with PVB indicating increased oxidative stress. PVB treatment significantly decreased the succinate dehydrogenase activity with a significant increase in lactate dehydrogenase, glucose-6-phosphate dehydrogenase, aspartate aminotransaminase, alanine aminotransaminase, and glutamate dehydrogenase activities indicating deranged hepatic metabolism. Melatonin administration, on the other hand was found to significantly improve PVB-Induced biochemical changes, bringing them closer to the controls. The results from the study provide evidence that treatment with PVB affects hepatic metabolism in rats by inducing oxidative stress followed by decreasing mitochondrial oxidation and also point towards the clinical potential of melatonin as an adjuvant therapy to conventional chemotherapeutic regimens. J. Exp. Zool. 9999A: 1-8, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
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    • "Likewise, antioxidant capability has been reported to be greater in tumoral cells than in normal cells [34], but this effect is surpassed by the OS induced by AD. Short-lived cells or cells with higher renewal rates which are constantly being regenerated are the most affected, in addition to the fact that there are other undesirable effects associated with free radical generation, such as doxorubicin-induced cardiac toxicity (rapid heartbeat, heart failure), bleomycin-induced pulmonary fibrosis, and cisplatin-induced ototoxicity [37–39]. "
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    • "The liver is highly susceptible to oxidative reactions as it is the main center of metabolism of most of the substances in the body, including exogenous substances like drugs. Usually nephrotoxicity is monitored during treatment with CDDP, but hepatotoxicity does not receive much attention [6]. It has been reported that oxidative stress through the generation of reactive oxygen species (ROS) decreased antioxidant defense systems, including antioxidant enzymes and nonenzymatic molecule glutathione (GSH), which are all major aspects of CDDP toxicity [7] [8]. "
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