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Hepatic cytochrome P450s (CYPs) play an important role in the metabolism of plant carcinogen, aristolochic acid I (AAI). In the present study, we employed hepatic NADPH-cytochrome P450 reductase null (HRN)  gpt  delta transgenic mice to investigate the role of hepatic CYPs in the metabolism of AAI. DNA adduct formation, gene mutation, and tumor induction in the liver and kidneys were analyzed. Pharmacokinetic analyses were performed and tissue levels of AAI were determined.    Results  Pretreatment with β-naphthoflavone in wild type  gpt  delta transgenic mice (BNF-WT mice) could increase the rate of clearance of AAI in blood and tissues, and decrease the formation of AAI-DNA adducts in kidney. In contrast, there was reduced clearance of AAI in HRN  gpt  delta mice, which showed increased concentration of AAI in tissues and increased levels of DNA adducts. The mutant frequencies of  gpt  gene, induced by AAI, in the kidneys of HRN  gpt  delta mice were significantly higher than that in WT mice. In the tumor induction assay, after treatment for 2 months with daily doses of 5 mg/kg AAI, mice were kept under observation for 7 months. During this period, papillomatous changes occurred in the forestomach of both WT-AAI mice and HRN  gpt  delta-AAI mice. Squamous cell carcinomas were found in the forestomach of 2 HRN  gpt  delta-AAI mice, which had also metastasized to other tissues. In addition, adenomas were found in 2 of 8 HRN  gpt  delta-AAI mice, in the absence of squamous cell carcinomas.    Conclusion  These results indicated that the main role of hepatic CYPs is to aid in the excretion of AAI, and to protect the target organs against AAI induced DNA adduct formation, mutagenesis, and tumorigenesis.    Electronic supplementary material  The online version of this article (doi:10.1186/s41021-015-0010-z) contains supplementary material, which is available to authorized users.

Role of hepatic cytochrome P450 enzymes in the detoxication of aristolochic acid I; effects on DNA adduct, mutation, and tumor formation