PEROXISOMAL GENES AND ENVIRONMENTAL CARCINOGENESIS

几种降血脂药物和环境污染物诱导肝硬化 过氧化物酶体增殖和肝细胞癌， 啮齿动物 这些药物诱导肝细胞凋亡的机制 癌是未知的，但可能与生化变化有关 过氧化物酶体增殖物诱导，因为大多数研究没有显示它们 有遗传毒性 过氧化物酶体增殖剂诱导细胞增殖， 几种基因的表达增加，包括 过氧化物酶体β-氧化途径和细胞色素P-450 4A家族。 但由于表达的基因很多，很难确定 该特定基因负责肝肿瘤的诱导。 将单个基因插入小鼠或大鼠体内， 创造转基因动物可能有助于解决这个问题。 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。 因此我们 建议1）生产转基因小鼠和大鼠的基因， 过氧化物酶体增殖物诱导蛋白脂肪酰辅酶A氧化酶， 过氧化物酶体双功能酶和细胞色素P-450 4A 1。 的基因 这些蛋白质已经连接到PEPCK控制元件上， 用于创建具有肝脏特异性表达 这些基因;和2）检查生物化学效应产生的增加 这些基因在肝脏中的表达，包括毒性的诱导 和细胞增殖，以及诱导氧化损伤， DNA氧化损伤和脂质过氧化。 这些研究将表明， 过氧化物酶体增殖物诱导的基因负责生化 过氧化物酶体增殖剂给药后观察到的变化。 产生这些变化的特定基因可以在未来进行检查 研究以确定它们的表达增加是否足以诱导 或促进肝细胞癌。

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.