The mechanism and risk factors of clopidogrel-induced liver injury

Abstract

Context and objective: Clopidogrel (CLP) is a prodrug which is widely used as a platelet aggregation inhibitor. Hepatotoxicity is rare but a potentially serious adverse reaction that is associated with CLP. Thiophene in CLP (the thienopyridine derivative) is a group that is easily oxidated by cytochrome P450 enzymes (CYP450s) to generate reactive metabolites (RMs), it may be implicated in the mechanism of CLP-induced hepatotoxicity. CYP2C19 and CYP2B6 are important CYP450s involved in the metabolism and activation of CLP, and the aim of this study is to investigate whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced liver injury. Method: Primary rat hepatocytes are applied to evaluate the hepatotoxicity of CLP. Glutathione-depleted mouse model is used to evaluate whether this toxicity of CLP is metabolized by CYP450s. We also used HepG2 cells co-incubated with recombinant CYP2B6 and CYP2C19 enzymes to further assess whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced hepatocellular toxicity. Result: CLP in high dose (100 μM and 300 μM) showed cytotoxicity in primary rat hepatocytes assay. Administration of CLP with l-buthionine-S, R-sulfoxinine (BSO) for seven days enhanced the liver injury of CLP. The level of ALT, AST and TBIL in plasma increased significantly, and the histopathological results showed the obvious liver injury; Pretreatment of 1-aminobenzotriazole, a nonspecific inhibitor of CYP450s, suppressed CLP-induced hepatotoxicity; CLP showed a dose-dependent toxicity in HepG2/CYP2C19 enzyme and HepG2/CYP2B6 enzyme models. Conclusion: High activities of CYP2C19 and CYP2B6 are the risk factors for hepatocellular toxicity of CLP.

• Clopidogrel
• drug-induced liver injury
• reactive metabolites
• cytochrome P450 enzymes
• CYP2C19
• CYP2B6

Declaration of interest

The authors report no declaration of interest. This study was supported by National Natural Science Foundation of China [NSFC, No. 81373890]; The Open Topic Fund for State Key Laboratory of Bioactive Substance and Function of Natural Medicines [No. GTZK201514]; The National Training Programs of Innovation and Entrepreneurship for Undergraduates [No. 201510063009]; The Program for Changjiang Scholars and Innovative Research Team in University [PCSIRT, No. IRT_14R41].