Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Int J Cancer. 2013 May 1;132(9):2065-75. doi: 10.1002/ijc.27897. Epub 2012 Dec 4.
Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1, CYP1B1) and other enzymes can activate PAHs to reactive oxygenated intermediates involved in mutagenesis and tumor initiation; also, CYP1 enzymes can detoxify PAHs. Cyp1(+/+) wild-type (WT) and Cyp1b1(-/-) knockout mice receiving oral BaP (12.5 mg/kg/day) remain healthy for >12 months. In contrast, we found that global knockout of the Cyp1a1 gene (1a1KO) results in proximal small intestine (PSI) adenocarcinoma within 8-12 weeks on this BaP regimen; striking compensatory increases in PSI CYP1B1 likely participate in initiation of adenocarcinoma in 1a1KO mice. Cyp1a1/1b1(-/-) double-knockout (DKO) mice on this BaP regimen show no PSI adenocarcinoma, but instead preputial gland duct (PGD) squamous cell carcinoma (SCC) occurs by 12 weeks. Herein, we compare microarray expression of PGD genes in WT, 1a1KO and DKO mice at 0, 4, 8, 12 and 16 weeks of oral BaP; about four dozen genes up- or down-regulated during most critical time-points were further verified by qRT-PCR. In DKO mice, CYP3A59 was unequivocally identified as the BaP-inducible and BaP-metabolizing best candidate responsible for initiation of BaP-induced SCC. Striking increases or decreases were found in 26 cancer-related genes plus eight Serpin genes in DKO, but not in 1a1KO or WT, mice on this BaP regimen; of the 26, 8 were RAS-related oncogenes. The mechanism by which cancer-related genes are responsible for SCC tumor progression in the PGD remains to be elucidated.
苯并[a]芘（BaP）是一种典型的多环芳烃（PAH），存在于燃烧过程中。细胞色素 P450 1A1 和 1B1 酶（CYP1A1、CYP1B1）和其他酶可以将 PAH 激活为参与突变和肿瘤起始的活性氧化中间产物；此外，CYP1 酶可以解毒 PAH。接受口服 BaP（12.5mg/kg/天）的 Cyp1(+/+)野生型（WT）和 Cyp1b1(-/-)基因敲除小鼠持续健康超过 12 个月。相比之下，我们发现 Cyp1a1 基因的全局敲除（1a1KO）导致在该 BaP 方案下 8-12 周内近端小肠（PSI）腺癌；PSI CYP1B1 的惊人代偿性增加可能参与了 1a1KO 小鼠腺癌的起始。在该 BaP 方案下，Cyp1a1/1b1(-/-)双基因敲除（DKO）小鼠没有发生 PSI 腺癌，但 12 周时发生了包皮腺导管（PGD）鳞状细胞癌（SCC）。在此，我们比较了 WT、1a1KO 和 DKO 小鼠在口服 BaP 0、4、8、12 和 16 周时 PGD 基因的微阵列表达；在大多数关键时间点上调或下调的大约四十几个基因进一步通过 qRT-PCR 进行了验证。在 DKO 小鼠中，CYP3A59 被明确鉴定为 BaP 诱导和 BaP 代谢的最佳候选物，负责 BaP 诱导 SCC 的起始。在 DKO 小鼠中，发现了 26 个癌症相关基因加上 8 个 Serpin 基因的显著增加或减少，但在 1a1KO 或 WT 小鼠中没有发现这种情况；在这 26 个基因中，有 8 个是 RAS 相关癌基因。在 PGD 中，癌症相关基因如何导致 SCC 肿瘤进展的机制仍有待阐明。
