title: Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice.
abstract: OBJECTIVE
  Monocrotaline (MCT) in plants of the genus Crotalaria induces significant toxicity in multiple organs including the liver, lung and kidney. Metabolic activation of MCT is required for MCT-induced toxicity. In this study, we attempted to determine whether the toxicity of MCT in kidney was a consequence of the metabolic activation of MCT in the liver.
  
  
  METHODS
  Liver-specific cytochrome P450 reductase-null (Null) mice, wild-type (WT) mice and CYP3A inhibitor ketoconazole-pretreated WT (KET-WT) mice were examined. The mice were injected with MCT (300, 400, or 500 mg/kg, ip), and hepatotoxicity and nephrotoxicity were examined 24 h after MCT treatment. The levels of MCT and its metabolites in the blood, liver, lung, kidney and bile were determined using LC-MS analysis.
  
  
  RESULTS
  Treatment of WT mice with MCT increased the serum levels of alanine aminotransferase, hyaluronic acid, urea nitrogen and creatinine in a dose-dependent manner. Histological examination revealed that MCT (500 mg/kg) caused severe liver injury and moderate kidney injury. In contrast, these pathological abnormalities were absent in Null and KET-WT mice. After injection of MCT (400 and 500 mg/kg), the plasma, liver, kidney and lung of WT mice had significantly lower MCT levels and much higher N-oxide metabolites contents in compared with those of Null and KET-WT mice. Furthermore, WT mice had considerably higher levels of tissue-bound pyrroles and bile GSH-conjugated MCT metabolites compared with Null and KET-WT mice.
  
  
  CONCLUSIONS
  Cytochrome P450s in mouse liver play a major role in the metabolic activation of MCT and thus contribute to MCT-induced renal toxicity.
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Cheng-gang
authors.initials: CG
authors.lastname: Li
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Li-kun
authors.initials: LK
authors.lastname: Gong
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Chen-chen
authors.initials: CC
authors.lastname: Feng
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Chun-zhu
authors.initials: CZ
authors.lastname: Li
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Man
authors.initials: M
authors.lastname: Gao
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luan
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Xin-ming
authors.initials: XM
authors.lastname: Qi
authors.affiliation: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016686:Monocrotaline / Q000494:pharmacology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*
chemical_list: D016686:Monocrotaline; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase