Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation

• DOI: 10.1124/mol.65.5.1225
• Publication Date: 2004-04-21T02:27:52Z
• Authors: Shigeyuki Uno; Timothy P. Dalton; Sandrine Derkenne; Christine P. Curran; Marian L. Miller; Howard G. Shertzer; Daniel W. Nebert
• Keywords: Piperonyl butoxide

The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo[<i>a</i>]pyrene (BaP), to DNA- and protein-binding intermediates that are associated with toxicity, mutagenesis, carcinogenesis. As a result, it is widely accepted CYP1A1 potentiates the toxicity of this class chemicals. In distinct contrast, we show here inducibility essential in detoxication oral BaP. We compared <i>Cyp1a1</i>(-/-) knockout mice, having genetic absence enzyme, <i>Cyp1a1</i>(+/+) wild-type mice. At an BaP dose 125 mg/kg/day, mice died within 30 days whereas displayed no outward signs toxicity. rate clearance was 4-fold slower than cause death receiving seemed be immunotoxicity, toxic chemical depression bone marrow; some effects were noted at as low 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels all tissues assayed, exception small intestine, which probably major site metabolism Different patterns also observed between two genotypes Despite previous vitro cell culture have shown participatory role for present data indicate that, intact animal, inducible extremely important protection against