Benzo[a]pyrene-induced toxicity: paradoxical protection in Cyp1a1(-/-) knockout mice having increased hepatic BaP-DNA adduct levels

Biochem Biophys Res Commun. 2001 Dec 21;289(5):1049-56. doi: 10.1006/bbrc.2001.6110.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

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


  • Carcinogens, Environmental
  • DNA Adducts
  • RNA, Messenger
  • benzo(a)pyrene-DNA adduct
  • Benzo(a)pyrene
  • Aryl Hydrocarbon Hydroxylases
  • Cyp1b1 protein, mouse
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1