Cytochrome P450 CYP1B1 determines susceptibility to 7,12-dimethylbenz[a]anthracene-induced lymphomas
Cytochrome P450 CYP1B1 determines susceptibility to 7,12-dimethylbenz[a]anthracene-induced lymphomas
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DOI：
10.1073/pnas.96.5.1977
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发表时间：
1999-03-02
影响因子：
11.1
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
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作者：
Buters, JTM;Sakai, S;Gonzalez, FJ
由胚胎干细胞中的靶向基因破坏产生的CYP1B1缺失的小鼠，以预期的频率从杂合子配对中出生，没有可观察到的表型，因此证实了CYP1B1不是小鼠发育所必需的。在用芳烃受体激动剂2，3，7，8-四氯二苯并对二恶英处理的胚胎成纤维细胞(EF)或不同组织(如肺)中不能检测到CYP1B1，而同等的野生型EF细胞表达基础和实质可诱导的CYP1B1，肺表达可诱导的CYP1B1，在野生型小鼠的肝脏、肾脏和肺中诱导的CYP1A1的水平远远高于CYP1B1缺失的小鼠，并在CYP1B1缺失的小鼠中得到类似程度的诱导。7，12-二甲基苯并[a]菲(DMBA)对表达细胞色素P1B1而不表达细胞色素P1A1的野生型EFS有毒性作用。这些细胞有效地代谢DMBA，这与CYP1B1参与产生致癌前物质3，4-二氢二醇作为主要代谢物是一致的，而CYP1B1缺失的EF没有明显的代谢，并且对DMBA介导的毒性具有抵抗力。当野生型小鼠灌胃高水平的DMBA时，70%的小鼠患上高度恶性的淋巴瘤，而只有7.5%的CYP1B1基因缺失的小鼠有淋巴瘤，皮肤增生和肿瘤在野生型小鼠中也更常见。这些结果表明，仅位于肝外部位的CYP1B1介导了DMBA的致癌作用。令人惊讶的是，在体外具有高DMBA代谢率的CYP1A1不足以实现这种致癌作用，这表明了肝外P450在确定化学致癌物易感性方面的重要性，并验证了P450表达与人类癌症风险之间的联系的研究。
CYP1B1-null mice, created by targeted gene disruption in embryonic stem cells, were born at the expected frequency from heterozygous matings with no observable phenotype, thus establishing that CYP1B1 is not required for mouse development. CYP1B1 was not detectable in cultured embryonic fibroblast (EF) or in different tissues, such as lung, of the CYP1B1-null mouse treated with the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin whereas the equivalent wild-type EF cells express basal and substantial inducible CYP1B1 and lung expresses inducible CYP1B1, CYP1A1 is induced to far higher levels than CYP1B1 in liver, kidney, and lung in wild-type mice and is induced to a similar extent in CYP1B1-null mice. 7,12-dimethylbenz[a]anthracene (DMBA) was toxic in wild-type EFs that express CYP1B1 but not CYP1A1. These cells effectively metabolized DMBA, consistent with CYP1B1 involvement in producing the procarcinogenic 3,4-dihydrodiol as a major metabolite, whereas CYP1B1-null EF showed no significant metabolism and were resistant to DMBA-mediated toxicity. When wild-type mice were administered high levels of DMBA intragastrically, 70% developed highly malignant lymphomas whereas only 7.5% of CYP1B1-null mice had lymphomas, Skin hyperplasia and tumors were also more frequent in wild-type mice. These results establish that CYP1B1, located exclusively at extrahepatic sites, mediates the carcinogenicity of DMBA. Surprisingly, CYP1A1, which has a high rate of DMBA metabolism in vitro, is not sufficient for this carcinogenesis, which demonstrates the importance of extrahepatic P450s in determining susceptibility to chemical carcinogens and validates the search for associations between P450 expression and cancer risk in humans.