Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity.
Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity.
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DOI：
10.1038/ki.2008.103
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发表时间：
2008-06
影响因子：
19.6
通讯作者：
Ying Xiao;M. Ge;X. Xue;Chaochen Wang;Hui Wang;Xiongwei Wu;Lixiang Li;Lin-lin Liu;X. Qi;Yunhai Zhang;Yan Li;H. Luo;T. Xie;J. Gu;J. Ren
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文献类型：
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作者：
Ying Xiao;M. Ge;X. Xue;Chaochen Wang;Hui Wang;Xiongwei Wu;Lixiang Li;Lin-lin Liu;X. Qi;Yunhai Zhang;Yan Li;H. Luo;T. Xie;J. Gu;J. Ren
细胞色素 P450 代谢天然存在的肾毒素马兜铃酸。使用肝脏特异性细胞色素 P450 还原酶缺失的小鼠，我们发现低但致死剂量的马兜铃酸 I 对野生型小鼠无效。 3-甲基胆蒽预处理诱导肝脏CYP1A显着提高了给予较高剂量的野生型小鼠的存活率，并且这些小鼠免受马兜铃酸I诱导的肾损伤。与对照和 3-甲基胆蒽预处理的野生型小鼠相比，无效小鼠中马兜铃酸 I 的清除速度较慢。与对照野生型小鼠相比，无效小鼠肾脏和肝脏中马兜铃酸 I 的水平要高得多，但 3-甲基胆蒽处理的马兜铃酸 I 水平要低得多。与未处理的小鼠相比，3-甲基胆蒽处理的野生型小鼠的肝微粒体具有更高的活性。最后，马兜铃酸 I 比其主要代谢物马兜铃内酰胺 I 具有更强的细胞毒性，并且在重建的肝微粒体-细胞质 (S9) 系统存在下，这种细胞毒性在人肾小管上皮 HK2 细胞中降低。这些结果表明，肝脏P450在将马兜铃酸I代谢成毒性较小的代谢物方面发挥着重要作用，因此在马兜铃酸I诱导的肾损伤中具有解毒作用。
Cytochrome P450s metabolize the naturally occurring nephrotoxin aristolochic acid. Using liver-specific cytochrome P450 reductase-null mice we found that a low but lethal dose of aristolochic acid I was ineffective in wild-type mice. Induction of hepatic CYP1A by 3-methylcholanthrene pretreatment markedly increased the survival rate of wild type mice given higher doses and these mice were protected from aristolochic acid I-induced renal injury. Clearance of aristolochic acid I in null mice was slower compared to control and the 3-methylcholanthrene-pretreated wild type mice. The levels of aristolochic acid I in the kidney and liver were much higher in null mice but much lower in 3-methylcholanthrene-treated compared to control wild type mice. Hepatic microsomes from 3-methylcholanthrene-treated wild type mice had greater activity compared to untreated mice. Finally, aristolochic acid I was more cytotoxic than its major metabolite aristolactam I and this cytotoxicity was decreased in human renal tubular epithelial HK2 cells in the presence of a reconstituted hepatic microsome-cytosol (S9) system. These results indicate that hepatic P450s play an important role in metabolizing aristolochic acid I into less toxic metabolites and thus have a detoxification role in aristolochic acid I-induced kidney injury.