TOXICITY OF CHEMICALS ASSOCIATED WITH LIPOPROTEINS

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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.