MECHANISMS OF CARCINOGENESIS--HALOGENATED BIPHENYLS

致癌机制--卤代联苯

• 批准号: 2098161
• 负责人: LARRY W ROBERTSON
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2098161
• 关键词: DNA damage; Salmonella; adduct; cell transformation; chemical carcinogen; chemical carcinogenesis; chemical structure function; epoxide hydrolase; epoxides; free radical oxygen; gas chromatography mass spectrometry; halobiphenyl /halotriphenyl compound; laboratory rat; micronucleus; mutagen testing; mutagens; nuclear magnetic resonance spectroscopy; quinones; radiotracer; toxin metabolism

Polyhalogenated biphenyls, particularly polychlorinated biphenyls (PCBs), are industrial chemicals which are stable and persist in our environment. Their lipophilicity and resistance to chemical or biological degradation result in their accumulation in fatty tissues of humans and other animals and eventual secretion into milk fat. These characteristics raise concern about the health risks associated with long-term exposure to these compounds. Numerous studies have found that PCBs and the closely-related polybrominated biphenyls (PBBs) induce hepatocellular carcinomas in mice and rats, but the mechanism by which they do so has not been determined. We and others have shown that PCBs/PBBs act as promoters of liver carcinogenesis; but their initiating or DNA-damaging activity has not been conclusively demonstrated. We therefore propose to test the hypotheses that biphenyl and halogenated biphenyls 1) induce mutations, cytogenetic damage and cell transformation in in vitro systems, 2) form quinoid metabolites that (at least in part) are responsible for genotoxic effects seen, 3) induce DNA adducts in rats. The potential of biphenyl and halogenated biphenyls to induce mutations in mammalian cells will be examined, while their ability to interact with cellular DNA will be monitored by sensitive 32P-postlabeling methods. Of particular interest is the identification of the reactive species responsible for the genotoxicity. Using these test systems, we shall define structure-activity relationships, identify critical metabolic parameters (which enzymes, cofactors are involved), identify mammalian targets and determine the structures of active metabolites. Our preliminary data indicate that several lower halogenated biphenyls are mutagenic in Salmonella and in V79 cells in the presence of an exogenous activation system. The spectra of genotoxicity seen with these compounds indicate that two mechanisms of activation (via expoxides and quinones) are operative. Our most recent data showing that mono- and dichlorobiphenyls are enzymatically activated to species that form adducts with guanine and/or adenine strongly support the involvement of quinones in the genotoxicity of these compounds. Clarification of the mechanism by which individual PCBs cause liver tumors will form a basis for the human health risk assessment for exposure to these chemicals.

多元释放的双苯基，尤其是多氯联苯（PCB），， 是稳定并在我们的环境中持续存在的工业化学品。 它们的亲脂性和对化学或生物降解的抵抗力 导致它们积聚在人类和其他动物的脂肪组织中 最终分泌到牛奶脂肪中。这些特征引起了人们的关注 关于与长期暴露有关的健康风险 化合物。 许多研究发现PCB和密切相关的 多溴双苯基（PBB）诱导小鼠肝细胞癌 和大鼠，但尚未确定他们这样做的机制。 我们和其他人表明，PCB/PBB充当肝脏的启动子 癌变；但是他们的启动或DNA损害活动尚未 最终证明了。 因此，我们建议测试 假设双苯基和卤代双苯基1）诱导突变， 细胞遗传学损伤和体外系统中的细胞转化，2）形式 （至少部分）负责遗传毒性的奎因代谢物 看到的效果，3）在大鼠中诱导DNA加合物。 双苯基的潜力 和卤代双苯基在哺乳动物细胞中诱导突变将是 检查了，虽然它们与细胞DNA相互作用的能力将是 通过敏感的32p固定标签方法监测。 特别感兴趣 是识别负责的反应性物种 遗传毒性。 使用这些测试系统，我们将定义 结构活性关系，识别关键代谢参数 （涉及哪种酶，辅助因子），确定哺乳动物靶标和 确定活性代谢物的结构。 我们的初步数据 表明几个较低的卤代双苯基在 在外源激活的情况下，沙门氏菌和V79细胞中 系统。 这些化合物看到的遗传毒性光谱表明 激活的两种机制（通过exepoxide和quinones）是 操作员。 我们最近的数据表明单氯苯基和二氯苯基 被酶促激活到形成鸟嘌呤加合物的物种 和/或腺嘌呤强烈支持奎因酮参与 这些化合物的遗传毒性。 阐明该机制 单个PCB导致肝肿瘤将成为人类健康的基础 暴露于这些化学物质的风险评估。