© 2003 by Oxford University Press
© 2003 Oxford University Press
ARTICLE |
4-Aminobiphenyl–Induced Liver and Urinary Bladder DNA Adduct Formation in Cyp1a2(–/–) and Cyp1a2(+/+) Mice
Affiliation of authors: Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH.
Correspondence to: Daniel W. Nebert, MD, Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267–0056 (e-mail: dan.nebert{at}uc.edu).
Background: Metabolites of the potent human carcinogen 4-aminobiphenyl (ABP) induce oxidative stress and form DNA adducts that are associated with hepatic and urinary bladder toxicity and bladder tumorigenesis. Results of in vitro and cell culture studies have suggested that cytochrome P450 1A2 (CYP1A2) is the major metabolic activator of ABP. We used Cyp1a2(–/–) knockout mice to examine the role of CYP1A2 in ABP–DNA adduct formation in the liver and the bladder. Methods: Cyp1a2(+/+) wild-type and Cyp1a2(–/–) mice (total of four mice per group) were treated topically with 10 mg/kg ABP for various times, with or without pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an inducer of CYP1A2 activity. We evaluated ABP-induced toxicity by carrying out quantitative histology (of the liver, skin, and bladder), oxidative stress by measuring hepatic thiol levels, and liver and bladder DNA adduct formation by using 32P-postlabeling. Data were analyzed by general linear models and analysis of variance. All statistical tests were two-sided. Results: At the experimental times selected, we observed no histologic evidence of toxicity in the liver, skin, or bladder. Overall, Cyp1a2(+/+) mice had fewer DNA adducts 24 hours after ABP treatment than similarly treated Cyp1a2(–/–) mice. Compared with male mice, female mice had more DNA adducts in the liver but fewer adducts in the bladder, regardless of Cyp1a2 genotype. TCDD pretreatment was associated with a decrease in ABP–DNA adduct levels overall. After 2 hours of ABP treatment, hepatic thiol levels underwent statistically significant declines of severalfold in Cyp1a2(+/+) and Cyp1a2(–/–) males and in Cyp1a2(–/–) females. Conclusions: Contrary to our expectations, CYP1A2 expression was not associated with ABP-induced hepatic oxidative stress or with ABP–DNA adduct formation. Either CYP1A2 is not the major metabolic activator of ABP or other enzymes metabolically activate ABP in mice in the absence of CYP1A2.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Tang, G. R. Zirpoli, K. Guru, K. B. Moysich, Y. Zhang, C. B. Ambrosone, and S. E. McCann Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 938 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Arlt, M. Stiborova, C. J. Henderson, M. Thiemann, E. Frei, D. Aimova, R. Singh, G. Gamboa da Costa, O. J. Schmitz, P. B. Farmer, et al. Metabolic activation of benzo[a]pyrene in vitro by hepatic cytochrome P450 contrasts with detoxification in vivo: experiments with hepatic cytochrome P450 reductase null mice Carcinogenesis, March 1, 2008; 29(3): 656 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Sugamori, D. Brenneman, S. Wong, A. Gaedigk, V. Yu, H. Abramovici, R. Rozmahel, and D. M. Grant Effect of Arylamine Acetyltransferase Nat3 Gene Knockout on N-Acetylation in the Mouse Drug Metab. Dispos., July 1, 2007; 35(7): 1064 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Ma and A. Y. H. Lu CYP1A Induction and Human Risk Assessment: An Evolving Tale of in Vitro and in Vivo Studies Drug Metab. Dispos., July 1, 2007; 35(7): 1009 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Sugamori, D. Brenneman, and D. M. Grant In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice Drug Metab. Dispos., October 1, 2006; 34(10): 1697 - 1702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Dragin, T. P. Dalton, M. L. Miller, H. G. Shertzer, and D. W. Nebert For Dioxin-induced Birth Defects, Mouse or Human CYP1A2 in Maternal Liver Protects whereas Mouse CYP1A1 and CYP1B1 Are Inconsequential J. Biol. Chem., July 7, 2006; 281(27): 18591 - 18600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Nebert Comparison of gene expression in cell culture to that in the intact animal: relevance to drugs and environmental toxicants. Focus on "Development of a transactivator in hepatoma cells that allows expression of phase I, phase II, and chemical defense genes" Am J Physiol Cell Physiol, January 1, 2006; 290(1): C37 - C41. [Full Text] [PDF]
|
|
|
|
|
|
D. W. Nebert, T. P. Dalton, A. B. Okey, and F. J. Gonzalez Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer J. Biol. Chem., June 4, 2004; 279(23): 23847 - 23850. [Abstract] [Full Text] [PDF]
|
|