1. ¹State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
2. ²Graduate School of the Chinese Academy of Sciences, Shanghai, China
3. ³Shanghai TenGen Biomedical Company, Shanghai, China
4. ⁴Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York, USA

Correspondence: J Ren, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, China. E-mail: jren@mail.shcnc.ac.cn; Dr J Gu, Wadsworth Center, New York State Department of Health, Empire State Plaza, Box 509, Albany, New York 12201-0509, USA. E-mail: jungu@wadsworth.org; Dr T Xie, Shanghai TenGen Biomedical Company, Room 206, 1011 Ha Lei Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, China. E-mail: txie@tengen-biomed.com

Received 20 November 2007; Revised 24 January 2008; Accepted 30 January 2008; Published online 26 March 2008.

Abstract

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.