ALTERED LIPID METABOLISM IN PEROXISOMAL PROLIFERATION

邻苯二甲酸酯，广泛分散的增塑剂 环境，以及几种临床使用的降高脂血症 药物，诱导过氧化物体，并已被牵连到 肝细胞癌。这些生物的机制 目前还没有明确的回应。然而，2-乙基己醇是一种主要的 常用增塑剂邻苯二甲酸二乙基己酯的代谢物， 抑制灌流肝脏中肝酮的生成。2- 乙基己醇还导致循环酮小体减少。 伴随着微泡脂质的快速积累 仅在活体肝小叶的门脉周围区域。 因此，本文件中概述的实验的目的 应用是评估过氧酶体的假说 增殖物最初抑制酮的生成并导致脂质 在肝脏中积聚。血脂的增加可能是一种常见的 导致对这些化合物的生物反应的影响。至 检验这一假设，我们将研究脂肪酸的变化 多种过氧化物体增殖物在人体内的代谢 肝脏灌流和活体内对不同反应的物种 增殖物(大鼠、仓鼠、豚鼠)。信息来自 这些研究最终将导致阐明 过氧化体增殖物诱导其毒性的机制(S) 生物效应，并因此可能提供一种合理的手段 以防止它们的毒性。

Phthalic acid esters, widely dispersed plasticizers in the environment, as well as several clinically used antihyperlipidemic drugs, induce peroxisomes and have been implicated in hepatocellular carcinoma. Mechanisms for these biological responses are not clear. However, 2-ethylhexanol, a primary metabolite of the common plasticizer diethylhexyl phthalate, inhibited hepatic ketogenesis in the perfused liver. 2- ethylhexanol also caused circulating ketone bodies to decline concomitantly with a rapid accumulation of microvesicular lipid exclusively in periportal regions of the liver lobule in vivo. Therefore, the purpose of the experiments outlined in this application is to evaluate the hypothesis that peroxisomal proliferators initially inhibit ketogenesis and cause lipid to accumulate in the liver. Increases in lipid may be a common effect leading to the biological response to these compounds. To test this hypothesis, we will study changes in fatty acid metabolism due to a variety of peroxisomal proliferators in perfused livers and in vivo in species with different responses to proliferators (rats, hamsters, guinea pigs). Information from these studies will lead ultimately to the elucidation of mechanism(s) by which peroxisomal proliferators elicit their toxic biological effects and may consequently, provide a rational means to prevent their toxicity.