DIET AND CARCINOGENESIS BY PEROXISOME PROLIFERATORS

饮食和过氧化物酶体增殖剂的致癌作用

基本信息

批准号：
2091238
负责人：
HOWARD P GLAUERT
金额：
$ 12.17万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-09-01 至 1995-03-31
项目状态：
已结题

项目摘要

Several hypolipidemic drugs, plasticizers, perfluorinated fatty acids, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinoma 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 they have never been shown to be genotoxic. Peroxisome proliferators induce cell proliferation and the increased expression of several proteins, including the enzymes of the peroxisomal beta-oxidation pathway, the carnitine acyltransferases, and cytochrome P-450IVA1. The induction of these enzymes causes metabolic changes in hepatocytes, including altered lipid metabolism and increased production of hydrogen peroxide. We therefore propose to test the hypotheses that peroxisome proliferators induce hepatic tumors by 1) the induction of increased hydrogen peroxide production, 2) the induction of long-term cell proliferation, and 3) an alteration of lipid metabolism so as to lead to altered eicosanoid levels. We have found the peroxisome proliferator perfluorodecanoic acid (PFDA) differs from other peroxisome proliferators by inhibiting peroxisomal beta-oxidation, by increasing glutathione concentrations, and by not having promoting activity. This unusual peroxisome proliferator will be examined (and compared to ciprofibrate) for 1) its mechanism of inhibiting peroxisomal beta-oxidation, and thus of inhibiting hydrogen peroxide production, 2) its ability to induce hepatocyte proliferation over a long period of time, 3) its mechanism of increasing cellular glutathione, which may play a role in hydrogen peroxide detoxification, and 4) its ability to induce genotoxicity in the form of hydroxymethyldeoxyuridine and 8-hydroxydeoxyguanosine. Selenium and vitamin I, which were found to alter ciprofibrate-induced carcinogenesis, will also be examined for their ability to influence cell proliferation by ciprofibrate. Finally, the effect of peroxisome proliferators on levels of eicosanoids in hepatocytes, and the effect of altering eicosanoid levels on the induction of peroxisomal enzyme activities, DNA synthesis, and tumor promotion by peroxisome proliferators will be studied. These studies are important for the elucidation of the mechanisms by which peroxisome proliferators induce tumors.

多种降血脂药物、增塑剂、全氟脂肪酸等其他化学物质诱导肝过氧化物酶体增殖和肝细胞当给啮齿动物施用时，会产生癌症。这些机制通过诱发肝细胞癌的药物尚不清楚，但可能与之相关过氧化物酶体增殖物引起的生化变化，因为它们具有从未被证明具有遗传毒性。过氧化物酶体增殖剂诱导细胞增殖和多种蛋白质表达增加，包括过氧化物酶体β-氧化途径的酶，肉毒碱酰基转移酶和细胞色素 P-450IVA1。这些酶的诱导引起肝细胞代谢变化，包括脂质代谢改变并增加过氧化氢的产量。因此我们建议检验过氧化物酶体增殖物诱发肝肿瘤的假设 1) 诱导过氧化氢产量增加，2) 诱导长期细胞增殖，3) 改变脂质代谢，从而导致类二十烷酸水平改变。我们已经找到了过氧化物酶体增殖剂全氟癸酸 (PFDA) 与其他物质不同通过抑制过氧化物酶体β-氧化来抑制过氧化物酶体增殖，增加谷胱甘肽浓度，并且不促进活动。将检查这种不寻常的过氧化物酶体增殖物（并且与环丙贝特相比）1）其抑制过氧化物酶体的机制 β-氧化，从而抑制过氧化氢的产生，2) 长期诱导肝细胞增殖的能力，3) 其增加细胞谷胱甘肽的机制，可能在过氧化氢解毒，4) 其诱导遗传毒性的能力以羟甲基脱氧尿苷和8-羟基脱氧鸟苷的形式存在。硒和维生素 I，被发现可以改变环丙贝特诱导的致癌作用，还将检查它们影响细胞的能力环丙贝特的增殖。最后，过氧化物酶体的作用增殖细胞对肝细胞中类二十烷酸水平的影响，以及改变类二十烷酸水平对过氧化物酶体酶的诱导过氧化物酶体增殖物的活性、DNA 合成和肿瘤促进将被研究。这些研究对于阐明这一问题具有重要意义过氧化物酶体增殖物诱发肿瘤的机制。