4epatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice  

作　　者：Jun YAO Cheng-gang LI Li-kun GONG Chen-chen FENG Chun-zhu LI Man GAO Yang LUAN Xin-ming Qi Jin REN 

机构地区：[1]Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica,Chinese Academy of Sciences, Shanghai 201203, China

出　　处：《Acta Pharmacologica Sinica》2014年第2期292-300,共9页中国药理学报（英文版）

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 nephrotoxic- ity were examined 24 h after MCT treatment. The levels of MCT and its metabolites in the blood, liver, lung, kidney and bile were deter- mined 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 mod- erate 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 pyr roles 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.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 nephrotoxic- ity were examined 24 h after MCT treatment. The levels of MCT and its metabolites in the blood, liver, lung, kidney and bile were deter- mined 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 mod- erate 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 pyr roles 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.

关 键 词：MONOCROTALINE pyrrolizidine alkaloid hepatic cytochrome P450s KETOCONAZOLE metabolic activation hepatic toxicity renaltoxicity 

分 类 号：S682.29[农业科学—观赏园艺] Q559.9[农业科学—园艺学]