ALTERED LIPID METABOLISM IN PEROXISOMAL PROLIFERATION

邻苯二甲酸酯，广泛分散在增塑剂中， 环境，以及几种临床使用的抗高血压药物 药物，诱导过氧化物酶体， 肝细胞癌 这些生物学机制 答复不明确。 然而，2-乙基己醇，主要的 常见增塑剂邻苯二甲酸二乙基己酯的代谢物， 抑制灌注肝脏中的肝酮生成。 2- 乙基己醇也引起循环酮体减少 伴随着微泡脂质的快速积累 仅在体内肝小叶的门静脉周围区域。 因此，本文中概述的实验目的 应用是评估过氧化物酶体的假设， 增殖物最初抑制酮生成并引起脂质 积聚在肝脏中。 血脂升高可能是一种常见的 导致对这些化合物的生物反应的作用。 到 为了验证这一假设，我们将研究 代谢由于各种过氧化物酶体增殖物， 灌注的肝脏和在体内的物种具有不同的反应， 增殖物（大鼠、仓鼠、豚鼠）。 信息从 这些研究将最终阐明 过氧化物酶体增殖物引起其毒性的机制 生物学效应，因此可能提供一种合理的方法 以防止其毒性。

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.