PEROXISOMAL GENES AND ENVIRONMENTAL CARCINOGENESIS

几种降血脂药物和环境污染物致肝损伤 过氧化物酶增殖体与肝细胞癌 啮齿动物。这些药物诱导肝细胞的机制 癌症尚不清楚，但可能与生化变化有关。 是由过氧化物体增殖物诱导的，因为大多数研究都没有表明它们 是遗传毒性的。过氧化物酶体增殖物诱导细胞增殖和 几个基因表达的增加，包括 过氧化物体β氧化途径与细胞色素P-4504A家族 然而，由于许多基因都是表达的，所以很难确定 哪个特定基因(S)负责诱导肝脏肿瘤的发生。 将单基因植入小鼠或大鼠体内以 创造转基因动物可能会解决这个问题。我们 假设特定基因的表达是导致 过氧化物酶体增殖物诱导肝肿瘤的研究。因此，我们 建议1)生产转基因小鼠和大鼠，并将其转化为 过氧化物酶体增殖物诱导的蛋白质脂肪酰辅酶A氧化酶 过氧化物体双功能酶和细胞色素P-450 4A1。人类的基因 这些蛋白质已经连接到PEPCK控制元件上，并正在 用于建立肝脏特异表达的转基因小鼠和大鼠 这些基因；以及2)检测由增加的 这些基因在肝脏中的表达，包括毒性的诱导 和细胞增殖，以及氧化损伤的诱导，如 DNA氧化损伤和脂质过氧化。这些研究将显示哪些 过氧化物酶体增殖物诱导的基因对生化反应起作用 使用过氧化物酶体增殖物后的变化。 产生这些变化的特定基因可以在未来进行检查。 研究确定它们的表达增加是否足以诱导 或者促进肝细胞癌。

Several hypolipidemic drugs and environmental contaminants induce hepatic peroxisome proliferation and hepatocellular carcinomas when administered to rodents. The mechanism by which these agents induce hepatocellular carcinomas is not known, but likely is related to biochemical changes induced by peroxisome proliferators, since most studies have not shown them to be genotoxic. Peroxisome proliferators induce cell proliferation and the increased expression of several genes, including the enzymes of the peroxisomal beta-oxidation pathway and the cytochrome P-450 4A family. However, because many genes are expressed, it is difficult to determine which specific gene(s) is responsible for the induction of hepatic tumors. The emergence of technology to insert single genes into mice or rats to create transgenic animals may allow the resolution of this question. We hypothesize that the expression of specific genes is responsible for the induction of hepatic tumors by peroxisome proliferators. We therefore propose to 1) produce transgenic mice and rats with the genes for the peroxisome proliferator-induced proteins fatty acyl CoA oxidase, the peroxisomal bifunctional enzyme, and cytochrome P-450 4A1. The genes for these proteins have been attached to PEPCK control elements and are being used to create transgenic mice and rats with liver-specific expression of these genes; and 2) examine biochemical effects produced by the increased expression of these genes in the liver, including the induction of toxicity and cellular proliferation, and the induction of oxidative damage such as oxidative DNA damage and lipid peroxidation. These studies will show which peroxisome proliferator-induced genes are responsible for the biochemical changes seen after the administration of peroxisome proliferators. Specific genes which produce these changes can then be examined in future studies to determine if their increased expression is sufficient to induce or promote hepatocellular carcinomas.