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

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.

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

“…Moreover, the differences between MCT models and human PAH should also be taken into consideration. MCT not only induces PAH in rats but also affects both the right and left ventricles and other organs such as the liver and kidney, which notably increases mortality [59,60]. Nevertheless, MCT-induced PAH appears to be curable by several agents in rats, which is different from PAH in humans [39].…”

The Hemodynamic Characteristics of Right Ventricle After Gradient Pulmonary Artery Banding in Rats

“…But there is some difference from human PAH by the presentation of an initial permeability lung edema, with early loss of the endothelial barrier and prominent in ammatory adventitial proliferation [17]. Nevertheless, MCT can cause injury in other organs such as liver and kidney [18], this model is not the perfect model to expression the progress of the right heart failure which induced by PAH.…”

Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450

“…9-Glutahionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine was detected as conjugated to glutathione in human liver microsomes and in the bile of rats treated that were with the pyrrolizidine alkaloids isoline, retrorsine, and monocrotaline [ 220 ]. Monocrotaline caused severe liver and moderate renal toxicity in mice; the degree of toxicity was abrogated by pretreatment with ketoconazole, a CYP3A4 inhibitor [ 168 ]. Correspondingly, the presence of N-oxide metabolites of monocrotaline was decreased by pretreatment with ketoconazole.…”

“…Dehydromonocrotaline and dehydrorectronecine are metabolites of monocrotaline. Dehydromonocrotaline and dehydrorectronecine, but not monocrotaline, caused toxicity in human hepatic sinusoidal endothelial cells and HepG2 cells [ 168 , 169 ]. Retrorsine inhibits the activity of CYP3A4, as measured by testosterone hydroxylation [ 37 ].…”