title: 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.
abstract: 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 approximately 25 and approximately 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.
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056, USA.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Uno
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Nadine
authors.initials: N
authors.lastname: Dragin
authors.forename: Christine P
authors.initials: CP
authors.lastname: Curran
authors.forename: Sandrine
authors.initials: S
authors.lastname: Derkenne
authors.forename: Marian L
authors.initials: ML
authors.lastname: Miller
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001822:Body Burden; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts; D017931:DNA Primers; D005838:Genotype; D007107:Immune System / Q000187:drug effects; D008658:Inactivation, Metabolic; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction
chemical_list: D018736:DNA Adducts; D017931:DNA Primers; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1