DIET AND CARCINOGENESIS BY PEROXISOME PROLIFERATORS

饮食和过氧化物酶体增殖剂的致癌作用

• 批准号: 3186019
• 负责人: HOWARD P GLAUERT
• 金额: $ 10.55万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3186019
• 关键词: antihyperlipoproteinemic agent; antioxidants; chemical carcinogenesis; disease /disorder model; hydrogen peroxide; hypolipidemia; lipofuscin; liver cells; neoplasm /cancer classification /staging; nutrition related neoplasm /cancer; oxidation; peroxisome; polyvinyls; preneoplastic state; selenium; tumor promoters; vitamin E deficiency

Several hypolipidemic drugs and industrial plasticizers induce hepatic peroxisome proliferation and hepatocellular carcinomas when fed to rodents. Since plasticizers are used extensively in plastics which contact food and since plasticizers can diffuse from plastics into food, the general population as well as people taking hypolipidemic drugs are exposed to significant amounts of these chemicals. Neither the mechanisms by which these agents, termed peroxisome proliferators, induce hepatocellular carcinomas nor the way in which diet may inhibit peroxisome proliferator-induced carcinogenesis have been determined. Peroxisome proliferators have been shown to act as promoters in liver carcinogenesis, but their initiating activity has never been conclusively demonstrated. Peroxisomal enzymes generate hydrogen peroxide, and increased formation of lipofuscin pigments (an indication of oxidative damage) is associated with the long-term administration of these agents. We therefore propose to test the hypotheses that 1) peroxisome proliferators act as initiators as well as promoters in hepatocarcinogenesis; 2) oxidative damage is responsible for the induction of hepatocarcinogenesis by peroxisome proliferators; and 3) essential dietary antioxidants such as selenium, vitamin E, or vitamin C will protect against oxidative damage induced by peroxisome proliferators and thus inhibit initiation or promotion by these agents. The peroxisome proliferator ciprofibrate will be fed to rats during the initiation phase of two-stage hepatocarcinogenesis and the induction of tumors and putative preneoplastic lesions will be determined. Products of cellular oxidation in hepatocytes after the administration of ciprofibrate to rats and to primary hepatocyte cultures will be measured. Finally, the effect of dietary antioxidants on ciprofibrate- induced hepatocarcinogenesis and on oxidative damage in hepatocytes will be studied. These results may make it possible to derive the benefits of these compounds without the risk of developing hepatic tumors simply by consuming higher amounts of essential dietary antioxidants, such as selenium or vitamins E or C.

几种降血脂药物和工业增塑剂诱发 肝过氧化物酶体增殖与肝细胞癌 当喂给啮齿动物时。 由于增塑剂广泛用于 接触食品的塑料，因为增塑剂会扩散 从塑料到食品，普通大众以及人们 服用降血脂药物时暴露于大量 这些化学品。 这些药物的机制， 称为过氧化物酶体增殖物，诱导肝细胞 癌症或饮食抑制过氧化物酶体的方式 增殖物诱导的致癌作用已被确定。 过氧化物酶体增殖剂已被证明可作为促进剂 肝癌发生，但其起始活性从未被证实 最终证明了。 过氧化物酶体酶产生 过氧化氢，并增加脂褐素的形成 色素（氧化损伤的迹象）与 长期服用这些药物。 我们因此 建议检验以下假设：1) 过氧化物酶体增殖物 作为肝癌发生的始发者和促进者； 2） 氧化损伤负责诱导 过氧化物酶体增殖剂导致肝癌发生；和 3) 必需的膳食抗氧化剂，例如硒、维生素 E 或 维生素 C 可以防止氧化损伤 过氧化物酶体增殖物，从而抑制启动或促进 由这些代理人。 过氧化物酶体增殖剂环丙贝特将 在两阶段的起始阶段喂食大鼠 肝癌的发生和肿瘤的诱导以及假定的 将确定癌前病变。 蜂窝产品 给予环丙贝特后肝细胞氧化 将测量对大鼠和原代肝细胞培养物的影响。 最后，膳食抗氧化剂对环丙贝特的影响 诱导肝癌发生和氧化损伤 将研究肝细胞。 这些结果可能使之成为可能 获得这些化合物的好处，而没有风险 仅仅通过大量摄入就会引发肝肿瘤 必需的膳食抗氧化剂，例如硒或维生素 E 或 C.