title: Role of hepatic cytochrome P450 enzymes in the detoxication of aristolochic acid I; effects on DNA adduct, mutation, and tumor formation.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025 China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luan
authors.affiliation: Center for Drug Safety and Evaluation Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Xing
authors.affiliation: Center for Drug Safety and Evaluation Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
authors.affiliation: Wadsworth Center, New York State Department of Health, Empire State Plaza, Box 509, Albany, NY 12201-0509 USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
keywords: Aristolochic acid I (AAI); DNA adduct; Gene mutation assay; Hepatic cytochrome P450 (CYP); Tumorigenesis; gpt delta mice