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