Abstract
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.
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Acknowledgements
This work was supported by Key Projects of National Science and Technology Pillar Program (2012ZX09301001-006 and 2012zx09302003) and the Public Service Platform Project of Shanghai Science and Technology Committee (11DZ2292500) We thank Prof Yi-zheng WANG and Guo-yu PAN for helpful advice.
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Yao, J., Li, Cg., Gong, Lk. et al. Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice. Acta Pharmacol Sin 35, 292–300 (2014). https://doi.org/10.1038/aps.2013.145
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DOI: https://doi.org/10.1038/aps.2013.145
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