title: The mechanism and risk factors of clopidogrel-induced liver injury.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  High activities of CYP2C19 and CYP2B6 are the risk factors for hepatocellular toxicity of CLP.
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.|b Tianjin State Key Laboratory of Modern Chinese Medicine , Tianjin , China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.
authors.forename: Guo
authors.initials: G
authors.lastname: Feng
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Cui
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.
authors.forename: Lijun
authors.initials: L
authors.lastname: An
authors.affiliation: a School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Nankai District , Tianjin , China and.|b Tianjin State Key Laboratory of Modern Chinese Medicine , Tianjin , China.
authors.forename: Xin
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000077144:Clopidogrel; D065702:Cytochrome P-450 CYP2B6 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008815:Mice, Inbred Strains; D008954:Models, Biological; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; D000077144:Clopidogrel; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: CYP2B6; CYP2C19; Clopidogrel; cytochrome P450 enzymes; drug-induced liver injury; reactive metabolites