TOXICITY OF CHEMICALS ASSOCIATED WITH LIPOPROTEINS

提出了一种假设，认为活性代谢物 苯并(A)芘(BP)可能被转运到结合在 与血浆脂蛋白的非共价关联。这一假设是 由先前的研究支持，这些研究表明BP在 血浆几乎完全与脂蛋白脂类和 更多证据表明，大量的活性代谢物 从肝脏、体内和体外从肝细胞释放BP。 由于肝脏是血浆脂蛋白的主要来源，因此 BP的代谢产物可能是由与脂蛋白结合的肝细胞分泌的。 如果BP的亲电代谢产物从肝细胞中通过 扩散后，它们会迅速被血浆脂蛋白吸收。这个 亲脂性致癌物质及其代谢物与 脂蛋白可能会产生深远的生物学后果，因为 大多数细胞表面存在的特异性受体 血浆脂蛋白的特异性结合和内化。实验 将进行研究结合致癌物的遗传毒性效应 到脂蛋白。我们将确定BP的吸收和代谢是如何通过 肝细胞暴露于BP与 脂蛋白，相对于暴露在水溶液中的BP。我们会 确定BP-二环氧化物对人成纤维细胞的遗传毒性 BP的主要致突变代谢物因暴露而显著改变 细胞与脂蛋白结合的BPDE与其在水中的毒性 解决方案。其他实验将确定在多大程度上，一个功能 脂蛋白受体是介导BP和BPDE毒性所必需的 当细胞暴露于这些致癌物时观察到的与 脂蛋白。我们将采用我们在我们的 实验室分离和培养人肝细胞，以确定 人肝细胞分泌的新生脂蛋白的类型 肝细胞结合受体的培养和性质 脂蛋白的内化。

A hypothesis is presented to suggest that active metabolites of benzo(a)pyrene (BP) maybe transported to extrahepatic tissues bound in non-covalent association with plasma lipoproteins. This hypothesis is supported by previous studies that indicate that BP is transported in the plasma almost exclusively in association with lipoprotein lipids and additional evidence which indicate that large amounts of active metabolites of BP are released from the liver, in vivo and from hepatocytes in vitro. Since the liver is the major source of plasma lipoproteins, electrophilic metabolites of BP may be secreted from hepatocytes bound to lipoproteins. If electrophilic metabolites of BP are released from hepatocytes by diffusion, they would be rapidly taken up by plasma lipoproteins. The association of lipophilic carcinogens and their metabolites with lipoproteins could have profound biological consequences because of the presence of specific receptors on the surface of most cells for the specific binding and internalization of plasma lipoproteins. Experiments will be conducted to investigate the genotoxic effects of carcinogens bound to lipoproteins. We will determine how the uptake and metabolism of BP by hepatocytes is affected by exposing them to BP in association with lipoproteins, relative to exposure to BP in aqueous solution. We will determine if the genotoxicity to human fibroblasts of BP-diolepoxide, the major mutagenic metabolite of BP, is significantly altered by exposing cells to BPDE bound to lipoproteins, relative to its toxicity in aqueous solution. Other experiments will determine to what extent, a functional lipoprotein receptor is necessary to mediate the BP and BPDE toxicity observed when cells are exposed to these carcinogens in association with lipoproteins. We will employ tehcniques that we have developed in our laboratory to isolate and culture human hepatocytes so as to determine the types of nascent lipoproteins that are secreted by human hepatocytes in culture and the nature of the hepatic receptors for the binding and internalization of lipoproteins.