Department of Environmental Health, and the Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056, USA.
Mol Pharmacol. 2013 Sep;84(3):304-13. doi: 10.1124/mol.113.086637. Epub 2013 Jun 12.
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 can ingest large oral BaP doses (125 mg/kg/d) 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 the proximal small intestine (PSI) in Cyp1a1(-/-) mice; Cyp1a1/1b1(-/-) double-knockout mice show no PSI cancer but develop squamous cell carcinoma of the preputial gland duct (PGD). BaP-metabolizing CYP1B1 in the PSI and CYP3A59 in the PGD are the most likely candidates to participate in tumor initiation in the epithelial cells of these two tissues; oncogenes and tumor-suppressor genes upregulated and downregulated 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.
苯并[a]芘（BaP）是一种典型的多环芳烃（PAH）；这种无处不在的环境致癌剂存在于烟草烟雾、木炭烤食物以及屋顶、操场和高速公路受多环芳烃污染的表面。野生型细胞色素 P450 1（Cyp1a2(-/-)、Cyp1b1(-/-)或 Cyp1a2/1b1(-/-) 基因敲除）以及肝细胞中 Cyp1a1 表达缺失的小鼠可以摄入大剂量的口服 BaP（125mg/kg/d）而没有明显的毒性。Cyp1a1(-/-)和 Cyp1a1/1a2(-/-)基因敲除以及胃肠道上皮细胞中 Cyp1a1 表达缺失的小鼠会发生免疫毒性，并在 32 天内死亡，这表明胃肠道诱导型 CYP1A1 绝对是口服 BaP 解毒所必需的。由于 CYP1B1 在免疫细胞中不能使 BaP 发生代谢激活，因此 Cyp1a1/1b1(-/-)和 Cyp1a1/1a2/1b1(-/-) 小鼠可以避免因 BaP 免疫抑制和早期死亡而获救。在 Cyp1a1(-/-)小鼠中，口服 BaP 剂量降低 10 倍会导致近端小肠腺癌（PSI）；Cyp1a1/1b1 双基因敲除小鼠没有 PSI 癌，但会发展为包皮腺导管鳞癌（PGD）。PSI 中的 BaP 代谢酶 CYP1B1 和 PGD 中的 CYP3A59 最有可能参与这两种组织上皮细胞的肿瘤起始；在这两种组织中，肿瘤发生过程中上调和下调的癌基因和肿瘤抑制基因是完全不同的。这种“口服 BaP Cyp1”小鼠模型代表了一种强大的教学工具，表明基因-环境相互作用取决于给药途径：相同的口服而非腹腔内 BaP 暴露会导致靶器官毒性和肿瘤类型的显著差异，这取决于剂量和 Cyp1 基因型。
