Oral benzo[a]pyrene in Cyp1 knockout mouse lines:: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body burden and clearance rate

CYP1A1 and CYP1B1 metabolically activate many polycyclic aromatic hydrocarbons (PAHs), including benzo[a] pyrene, to reactive intermediates associated with toxicity, mutagenesis, and carcinogenesis. Paradoxically, however, Cyp1a1(-/-) knockout mice are more sensitive to oral benzo[ a] pyrene exposure, compared with wild-type Cyp1a1(-/-) mice ( Mol Pharmacol 65: 1225, 2004). To further investigate the mechanism for this enhanced sensitivity, Cyp1a1(-/-), Cyp1a2(-/-), and Cyp1b1(-/-) single-knockout, Cyp1a1/1b1(-/-) and Cyp1a2/1b1(-/-) double-knockout, and Cyp1(-/-) wild-type mice were analyzed. After administration of oral benzo[ a] pyrene ( 125 mg/kg/day) for 18 days, Cyp1a1(-/-) mice showed marked wasting, immunosuppression, and bone marrow hypocellularity, whereas the other five genotypes did not. After 5 days of feeding, steady-state blood levels of benzo[ a] pyrene were similar to 25 and similar to 75 times higher in Cyp1a1(-/-) and Cyp1a1/1b1(-/-) mice, respectively, than in wild-type mice. Benzo[ a] pyrene-DNA adduct levels were highest in liver, spleen, and marrow of Cyp1a1(-/-) and Cyp1a1/1b1(-/-) mice. Many lines of convergent data obtained with oral benzo[ a] pyrene dosing suggest that: 1) inducible CYP1A1, probably in both intestine and liver, is most important in detoxication; 2) CYP1B1 in spleen and marrow is responsible for metabolic activation of benzo[a] pyrene, which results in immune damage in the absence of CYP1A1; 3) both thymus atrophy and hepatocyte hypertrophy are independent of CYP1B1 metabolism but rather may reflect long-term activation of the aryl hydrocarbon receptor; and 4) the magnitude of immune damage in Cyp1a1(-/-) and Cyp1a1/1b1(-/-) mice is independent of plasma benzo[a] pyrene and total-body burden and clearance. Thus, a balance between tissue-specific expression of the CYP1A1 and CYP1B1 enzymes governs sensitivity of benzo[a] pyrene toxicity and, possibly, carcinogenicity.