TY - JOUR T1 - Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication and Consequences--Cyp1 Knockout Mouse Lines as a Paradigm JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.086637 SP - mol.113.086637 AU - Daniel W. Nebert AU - Zhanquan Shi AU - Marina Galvez-Peralta AU - Shigeyuki Uno AU - Nadine Dragin Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/06/12/mol.113.086637.abstract N2 - Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH); this ubiquitous environmental carcinogenic agent is found in tobacco smoke, charcoal-grilled foods, and PAH-contaminated surfaces of roofs, playgrounds and highways. Cytochrome P450 1 wild-type, Cyp1a2(-/-), Cyp1b1(-/-), or Cyp1a2/1b1(-/-) knockouts, and mice with Cyp1a1 expression deleted in hepatocytes, are able to ingest large oral BaP doses (125 mg/kg/day) without apparent toxicity. Cyp1a1(-/-) and Cyp1a1/1a2(-/-) knockouts, and mice with Cyp1a1 expression deleted in gastrointestinal (GI) tract epithelial cells, develop immunotoxicity and die within 32 days, indicating that GI tract inducible CYP1A1 is absolutely required for detoxication of oral BaP. Cyp1a1/1b1(-/-) and Cyp1a1/1a2/1b1(-/-) mice are rescued from immunosuppression and early death, due to absent metabolic activation of BaP by CYP1B1 in immune cells. Ten-fold lower oral BaP doses result in adenocarcinoma of proximal small intestine (PSI) in Cyp1a1(-/-) mice; Cyp1a1/1b1(-/-) double-knockout mice show no PSI cancer, but develop squamous cell carcinoma of preputial gland duct (PGD). BaP-metabolizing CYP1B1 in PSI, and CYP3A59 in PGD, are most likely candidates that participate in tumor initiation in epithelial cells of these two tissues; oncogenes and tumor-suppressor genes up- and down-regulated during tumorigenesis are completely different between these tissues. This "oral BaP Cyp1" mouse paradigm represents a powerful teaching tool, showing that gene-environment interactions depend on route-of-administration: the same oral, but not intraperitoneal, BaP exposure leads to dramatic differences in target-organ toxicity and tumor type, as a function of dose and Cyp1 genotype. ER -