title: 4-aminobiphenyl-induced liver and urinary bladder DNA adduct formation in Cyp1a2(-/-) and Cyp1a2(+/+) mice.
abstract: 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.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tsuneoka
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Marian L
authors.initials: ML
authors.lastname: Miller
authors.forename: Corey D
authors.initials: CD
authors.lastname: Clay
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: Glenn
authors.initials: G
authors.lastname: Talaska
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D000611:Aminobiphenyl Compounds; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000235:genetics*; D018736:DNA Adducts / Q000096:biosynthesis*; D004785:Environmental Pollutants; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins; D012867:Skin / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D018736:DNA Adducts; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; C006757:4-biphenylamine; D019388:Cytochrome P-450 CYP1A2