hepaticcytochromep450splayamajorroleinmonocrotalineinducedrenaltoxicityinmice

	hepaticcytochromep450splayamajorroleinmonocrotalineinducedrenaltoxicityinmice
	Yao Jun; Li Chenggang; Gong Likun; Feng Chenchen; Li Chunzhu; Gao Man; Luan Yang; Qi Xinming; Ren Jin
刊名	actapharmacologicasinica
	2014
卷号	35 期号:2 页码:292
关键词	monocrotaline pyrrolizidine alkaloid hepatic cytochrome P450s ketoconazole metabolic activation hepatic toxicity renal toxicity
ISSN号	1671-4083
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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/287598]
专题	中国科学院上海药物研究所
作者单位	中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Yao Jun,Li Chenggang,Gong Likun,et al. hepaticcytochromep450splayamajorroleinmonocrotalineinducedrenaltoxicityinmice[J]. actapharmacologicasinica,2014,35(2):292.
APA	Yao Jun.,Li Chenggang.,Gong Likun.,Feng Chenchen.,Li Chunzhu.,...&Ren Jin.(2014).hepaticcytochromep450splayamajorroleinmonocrotalineinducedrenaltoxicityinmice.actapharmacologicasinica,35(2),292.
MLA	Yao Jun,et al."hepaticcytochromep450splayamajorroleinmonocrotalineinducedrenaltoxicityinmice".actapharmacologicasinica 35.2(2014):292.