Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1 Knockout Mouse Lines as a Paradigm

摘要: Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH); this ubiquitous environmental carcinogenic agent found in tobacco smoke, charcoal-grilled foods, and PAH-contaminated surfaces of roofs, playgrounds, highways. Cytochrome P450 1 wild-type, Cyp1a2(−/−), Cyp1b1(−/−), or Cyp1a2/1b1(−/−) knockouts, mice with Cyp1a1 expression deleted hepatocytes can ingest large oral BaP doses (125 mg/kg/d) without apparent toxicity. Cyp1a1(−/−) Cyp1a1/1a2(−/−) knockouts gastrointestinal (GI) tract epithelial cells develop immunotoxicity die within 32 days, indicating that GI inducible CYP1A1 absolutely required for detoxication BaP. Cyp1a1/1b1(−/−) Cyp1a1/1a2/1b1(−/−) are rescued from immunosuppression early death due to absent metabolic activation by CYP1B1 immune cells. Ten-fold lower result adenocarcinoma the proximal small intestine (PSI) mice; double-knockout show no PSI cancer but squamous cell carcinoma preputial gland duct (PGD). BaP-metabolizing CYP3A59 PGD most likely candidates participate tumor initiation these two tissues; oncogenes tumor-suppressor genes upregulated downregulated during tumorigenesis completely different between tissues. This “oral Cyp1” mouse paradigm represents powerful teaching tool, showing gene-environment interactions depend on route-of-administration: same oral, not intraperitoneal, exposure leads dramatic differences target-organ toxicity type as function dose Cyp1 genotype.