INDUCTION OF CARCINOGEN BINDING PROTEINS

描述（改编自申请人摘要）：持久性 有机氯（OC）和多环芳烃（PAH）是 广泛的化学致癌物，经常共同出现在污染 水生环境 肿瘤发生率增加， 在这些地方栖息的野生鱼类中的致癌物残留物， 健康风险难以评估。 该提案的重点是 增加对肝脏摄取和细胞内转运的理解 有机氯化合物和遗传毒性多环芳烃在虹鳟鱼肝脏。 比较研究 也提出了使用RAT。 申请人假设OC 暴露诱导蛋白质结合并可能运输致癌物 在肝细胞内。 刺激细胞内结合和加工 致癌物的这种诱导涉及至少三个健康风险 的方式 (1)这些蛋白质可能在有机碳的生物积累中起关键作用 和多环芳烃的鱼类，这可能会导致营养转移，这些 材料给人类。 这些药物摄入的传统解释 专注于脂质分配。 更好地了解 亲脂性致癌物在鱼体内的处置机制是 这对于建立适当的生物累积模型十分重要。 (2)的 环境中的有机碳和多环芳烃在野生鱼类肿瘤发病率中的作用， 随着相互作用机制的定义，更好地评估。 申请人 建议虹鳟鱼肿瘤研究，将检查致癌性， OC，它们对PAH诱导的癌症发生的影响， PAH诱导的癌症的增殖/进展活性。 结果进行 肿瘤研究将根据我们了解到的 OC诱导的致癌物结合蛋白。 (3)虹鳟鱼模型是 对化学致癌作用的基础研究具有重要价值。 的有效性 将鱼类致癌物结合蛋白的信息外推到 人类健康将通过对大鼠的比较研究直接评估。 虹鳟鱼的一个重要属性，用于研究致癌物 结合/转运蛋白是诱导这些蛋白的潜力 而不诱导细胞色素P450系统。 这提供了一个机会 研究致癌物在小鼠体内的致瘤性和生化毒理学， 系统，其中结合和/或运输，而不是生物转化， 优先调制。

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.