期刊
KIDNEY INTERNATIONAL
卷 73, 期 11, 页码 1231-1239出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2008.103
关键词
aristolochic acid nephropathy; CYP1A; CPR null mice; kidney toxicity; metabolism
资金
- NIA NIH HHS [AG026329] Funding Source: Medline
- NATIONAL INSTITUTE ON AGING [R03AG026329] Funding Source: NIH RePORTER
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-methylcholanthrenetreated 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.
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