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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    • "Although several studies have shown that reactive oxygen species (ROS) or free radicals are closely related to the nephrotoxicity induced by CP (Liu et al., 2008; Baliga et al., 1998), the detailed mechanisms of CP-induced renal tubular toxicity have not been fully understood . However, in the literature, CP-induced hepatotoxicity is enhanced by elevated expression of cytochrome P450 (CYP) 2E1 (Lu and Cederbaum, 2006); and it has been reported that CYP2E1 contributes to CP nephrotoxicity (Liu et al., 2002). "
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    ABSTRACT: Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, but it has dose-dependent renal tubular toxicity. Previous studies have shown that induction of cytochrome P450 (CYP) by CP may play a role in the renal injury of CP. The aim of this study was to investigate the relationship between CP-induced toxicity and CYP4A11 expression in human renal tubular epithelial cells (HK-2). 20-Hydroxyeicosatetraenoic acid (20-HETE) is a CYP4A11 metabolite of arachidonic acid that plays an important role in renal injury. The activity of lactate dehydrogenase (LDH) was determined by spectrophotometer. CYP4A11 expression was analyzed by immunocytochemistry. CYP4A11 mRNA and protein expression were evaluated by RT-PCR and Western blot analyses. Results showed that 20-HETE (1, 10, 50 μM), a CYP4A11 metabolite of arachidonic acid, significantly increased lactate dehydrogenase (LDH) release in these cells. When CP (10-4 M) and 20-HETE (1, 10, 50 μM) were co-applied to these cells, CP-induced LDH release was significantly exaggerated by 20-HETE. Furthermore, clofibrate, a CYP4A inducer, also increased LDH release in CP-treated cells. In contrast, the CYP4A inhibitor N-Hydrocy-N'-(-4-butyl-2-methylphenyl) formamidine (HET-0016) decreased LDH release in CP-treated cells. Immunocytochemical analysis showed that CYP4A11expression was much stronger in CP- (10-4 M) treated cells than that in clofibrate-treated cells. Further RT-PCR and Western blot analyses demonstrated that CYP4A11 mRNA and protein expression were significantly up-regulated in CP- (10-4 M) treated cells compared to the clofibrate group. The findings of this study indicate that CP is a potent inducer of CYP4A11, and it exerts its toxic functions via the induction of CYP4A11 and 20-HETE generation.
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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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