Title: Benzo[a]pyrene-induced toxicity: paradoxical protection in Cyp1a1(-/-) knockout mice having increased hepatic BaP-DNA adduct levels.
Authors: Uno, S; Dalton, T P; Shertzer, H G; Genter, M B; Warshawsky, D; Talaska, G; Nebert, D W
Published In Biochem Biophys Res Commun, (2001 Dec 21)
Abstract: Previous studies have shown that cytochrome P450 1A1 (CYP1A1), CYP1B1, and prostaglandin-endoperoxide synthase (PTGS2) are inducible by benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), and all three metabolize BaP to reactive DNA-binding intermediates and excreted products. Because these three enzymes show differing patterns of basal levels, inducibility, and tissue-specific expression, animal studies are necessary to delineate the role of CYP1A1 in BaP-mediated toxicity. In mice receiving large daily doses of BaP (500 mg/kg i.p.), Cyp1a1(-/-) knockout mice are protected by surviving longer than Cyp1a1(+/-) heterozygotes. We found that a single 500 mg/kg dose of BaP induces hepatic CYP1A1 mRNA, protein, and enzyme activity in Cyp1a1(+/-) but not in Cyp1a1(-/-) mice; TCDD pretreatment increases further the CYP1A1 in Cyp1a1(+/-) but not Cyp1a1(-/-) mice. Although a single 500 mg/kg dose of BaP was toxic to Cyp1a1(+/-) mice (serum liver enzyme elevated about 2-fold above control levels at 48 h), Cyp1a1(-/-) mice displayed no hepatotoxicity. Unexpectedly, we found 4-fold higher BaP-DNA adduct levels in Cyp1a1(-/-) than in Cyp1a1(+/-) mice; TCDD pretreatment lowered the levels of BaP-DNA adducts in both genotypes, suggesting the involvement of other TCDD-inducible detoxification enzymes. BaP was cleared from the blood much faster in Cyp1a1(+/-) than Cyp1a1(-/-) mice. Our results suggest that absence of the CYP1A1 enzyme protects the intact animal from BaP-mediated liver toxicity and death, by decreasing the formation of large amounts of toxic metabolites, whereas much slower metabolic clearance of BaP in Cyp1a1(-/-) mice leads to greater formation of BaP-DNA adducts.
PubMed ID: 11741297
MeSH Terms: Animals; Aryl Hydrocarbon Hydroxylases*; Benzo(a)pyrene/administration & dosage; Benzo(a)pyrene/metabolism*; Benzo(a)pyrene/pharmacokinetics; Benzo(a)pyrene/toxicity*; Carcinogens, Environmental/administration & dosage; Carcinogens, Environmental/pharmacokinetics; Carcinogens, Environmental/toxicity*; Cytochrome P-450 CYP1A1/deficiency*; Cytochrome P-450 CYP1A1/genetics*; Cytochrome P-450 CYP1A1/metabolism; Cytochrome P-450 CYP1B1; DNA Adducts/metabolism*; Liver/drug effects*; Liver/metabolism*; Mice; Mice, Knockout; Models, Biological; RNA, Messenger/biosynthesis; RNA, Messenger/genetics