Cisplatin-mediated cytotoxicity through inducing CYP4A 11 expression in human renal tubular epithelial cells.

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Li J, Li D, Tie C, Wu J, Wu Q, Li Q

Cisplatin-mediated cytotoxicity through inducing CYP4A 11 expression in human renal tubular epithelial cells.

J Toxicol Sci. 2015 Dec;40(6):895-900. doi: 10.2131/jts.40.895.

PubMed ID

26558470 [ View in PubMed

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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 muM), 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 muM) 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Clofibrate	Cytochrome P450 4A11	Protein	Humans	Unknown	Substrate Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Clofibrate	Approved Investigational	CYP4A11	1579	upregulated	Clofibrate results in increased expression of CYP4A11 mRNA	1p33
Cisplatin	Approved	CYP4A11	1579	upregulated	Cisplatin results in increased expression of CYP4A11 mRNA	1p33