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.
