Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice | |
Yao, Jun; Li, Cheng-gang; Gong, Li-kun![]() ![]() ![]() | |
刊名 | ACTA PHARMACOLOGICA SINICA
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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 |
DOI | 10.1038/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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