Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice
Yao, Jun; Li, Cheng-gang; Gong, Li-kun; Feng, Chen-chen; Li, Chun-zhu; Gao, Man; Luan, Yang; Qi, Xin-ming; Ren, Jin
刊名ACTA PHARMACOLOGICA SINICA
2014-02
卷号35期号:2页码:292-300
关键词monocrotaline pyrrolizidine alkaloid hepatic cytochrome P450s ketoconazole metabolic activation hepatic toxicity renal toxicity
ISSN号1671-4083
DOI10.1038/aps.2013.145
文献子类Article
英文摘要Aim: 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. Conclusion: Cytochrome P450s in mouse liver play a major role in the metabolic activation of MCT and thus contribute to MCT-induced renal toxicity.
资助项目Key Projects of National Science and Technology Pillar Program[2012ZX09301001-006] ; Key Projects of National Science and Technology Pillar Program[2012zx09302003] ; Public Service Platform Project of Shanghai Science and Technology Committee[11DZ2292500]
WOS关键词NADPH-CYTOCHROME-P450 REDUCTASE GENE ; PYRROLIZIDINE ALKALOIDS ; RAT-LIVER ; MICROSOMAL CYTOCHROME-P450 ; VENOOCCLUSIVE DISEASE ; METABOLIC-ACTIVATION ; GLUTATHIONE ; CYP3A ; 3A ; DIHYDROPYRROLIZINE
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:5040836
出版者ACTA PHARMACOLOGICA SINICA
WOS记录号WOS:000330581300015
内容类型期刊论文
源URL[http://119.78.100.183/handle/2S10ELR8/277212]  
专题药物安全性评价中心
通讯作者Qi, Xin-ming
作者单位Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, State Key Lab New Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714
Yao, Jun,Li, Cheng-gang,Gong, Li-kun,et al. Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice[J]. ACTA PHARMACOLOGICA SINICA,2014,35(2):292-300.
APA Yao, Jun.,Li, Cheng-gang.,Gong, Li-kun.,Feng, Chen-chen.,Li, Chun-zhu.,...&Ren, Jin.(2014).Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice.ACTA PHARMACOLOGICA SINICA,35(2),292-300.
MLA Yao, Jun,et al."Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice".ACTA PHARMACOLOGICA SINICA 35.2(2014):292-300.
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