INDUCTION OF CARCINOGEN BINDING PROTEINS IN FISH

鱼中致癌物结合蛋白的诱导

• 批准号: 3253854
• 负责人: LAWRENCE R CURTIS
• 金额: $ 14.59万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-05 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253854
• 关键词: alternatives to animals in research; benzanthracenes; binding proteins; carbon tetrachloride poisoning; chemical carcinogen; chemical carcinogenesis; chlorobenzenes; cytochrome P450; cytotoxicity; enzyme mechanism; fish; hepatocellular carcinoma; heterocyclic polycyclic compound; intracellular transport; liver cells; toxin metabolism; water pollution

DESCRIPTION (Adapted from applicant's abstract): Persistent organochlorines (OCs) and polycyclic aromatic hydrocarbons (PAHs) are widespread chemical carcinogens which frequently co-occur in contaminated aquatic environments. Increased incidence of tumors and accumulation of carcinogen residues in feral fish inhabiting such sites presents a public health risk which is difficult to assess. This proposal focuses on increasing the understanding of hepatic uptake and intracellular transport of OCs and a genotoxic PAH in rainbow trout liver. Comparative studies using the rat are also proposed. The applicant hypothesizes that OC exposure induces proteins which bind and perhaps transport carcinogens within the hepatocyte. Stimulation of intracellular binding and processing of carcinogens by such induction relates to health risks in at least three ways. (1) These proteins likely play a key role in bioaccumulation of OCs and PAHs by fish which can presumably result in trophic transfer of these materials to humans. Traditional explanations for uptake of these agents by fish focused upon lipid partitioning. Improved understanding of the mechanistic basis for disposition of lipophilic carcinogens in fish is important for the development of adequate bioaccumulation models. (2) The role of environmental OCs and PAHs in tumor incidence in feral fish can be better assessed as mechanisms of interaction are defined. The applicant proposes rainbow trout tumor studies which will examine carcinogenity of OCs, their influence on initiation of PAH-induced cancer, and their activity in romotion/progression of PAH-induced cancer. Results of these tumor studies will be interpreted in light of what we learn about OC-induced carcinogen binding proteins. (3) The rainbow trout model is valuable for basic research on chemical carcinogenesis. The validity of the extrapolation of information on fish carcinogen binding proteins to human health will be directly assessed by comparative studies in the rat. An important attribute of the rainbow trout for studying carcinogen binding/transport proteins is the potential to induce these proteins without inducing the cytochrome P450 system. This provides an opportunity to study the tumorigenicity and biochemical toxicology of carcinogens in a system where binding and/or transport, rather than biotransformation, is preferentially modulated.

描述（改编自申请人的摘要）：持久 有机氯 (OC) 和多环芳烃 (PAH) 广泛存在的化学致癌物，经常在受污染的环境中同时出现 水生环境。 肿瘤发生率增加和肿瘤积累 栖息在这些地点的野鱼中残留的致癌物质向公众提出了警告 难以评估的健康风险。 该提案的重点是 增加对肝脏摄取和细胞内转运的了解 虹鳟鱼肝脏中的 OC 和遗传毒性 PAH。 比较研究 还建议使用大鼠。 申请人假设 OC 暴露会诱导蛋白质结合并可能转运致癌物质 肝细胞内。 刺激细胞内结合和加工 通过这种诱导产生的致癌物与至少三个方面的健康风险有关 方式。 (1) 这些蛋白质可能在 OC 的生物累积中发挥关键作用 鱼类体内的多环芳烃可能会导致这些物质的营养转移 人类的材料。 对这些药物吸收的传统解释 鱼类专注于脂质分配。 增进了对 鱼类体内亲脂性致癌物的处置机制基础是 对于建立适当的生物累积模型非常重要。 (2) 的 环境有机碳和多环芳烃在野鱼肿瘤发病中的作用可以 随着交互机制的定义，可以更好地进行评估。 申请人 提议进行虹鳟鱼肿瘤研究，以检查虹鳟鱼的致癌性 OCs，它们对 PAH 诱发癌症的影响，以及它们的作用 PAH 诱发的癌症的移动/进展的活性。 这些结果 肿瘤研究将根据我们所了解到的进行解释 OC诱导的致癌物结合蛋白。 (3) 虹鳟鱼模型为 对化学致癌作用的基础研究具有重要价值。 有效性 根据鱼类致癌物结合蛋白的信息推断 人类健康将通过大鼠的比较研究直接评估。 虹鳟鱼致癌物研究的一个重要属性 结合/转运蛋白是诱导这些蛋白质的潜力 不诱导细胞色素 P450 系统。 这提供了一个机会 研究致癌物的致瘤性和生化毒理学 结合和/或运输而不是生物转化的系统 优先调制。