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Possible Mechanism for di-(2-Ethylhexyl)phthalate-elicited Hepatic Peroxisome Proliferation

Administration of di-(2-ethylhexyi)phthalate (DEHP) to rodents results in proliferation of peroxisomes in the liver. DEHP is extensively metabolized by the liver (Albro etal., 1973). The principal metabolites of DEHPwere isolated from rat urine and added individually (at 0-0.5 mM) to cultured rat hepatocytes (n = 4-6). After 72 h of exposure the effect on cyanide-insensitive palmitoyl-CoA oxidation (PCO), a marker for peroxisome proliferation, was determined. Mono-(2-ethylhexyl)phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl)phthalate (metabolite IX) and mono-(2-ethyl-5-oxohexyl)phthalate (metabolite VI) produced dose-related increases in PCO. However, 2-ethylhexanol (2-EH), mono-(5-carboxy-2-ethylpentyl)phthalate (metabolite V) and mono-(3-carboxy-2ethylpropyl)phthalate (metabolite I) had little or no effect on PCO. Similar structure-activity relations were noted for induction of lauric acid hydroxylase activity (LAH). Oil red 0 staining of cultured rat hepatocytes revealed a marked increase in intracellular neutral lipid in cells exposed to MEHP (0.5 mM). This accumulation of lipid preceded the induction of both PCO and LAH. It is plausable then that a perturbation in hepatic lipid metabolism could lead to an increase in intracellular lipid and that the effects observed in the liver (peroxisome proliferation, LAH induction, etc.) are an adaptation to remove this lipid. The effects of metabolite VI on hepatic lipid metabolism were thus further investigated. Metabolite VI inhibited the oxidation of (1-’4C]palmitic acid by isolated rat hepatocytes. By using isolated rat liver mitochondria metabolite VI was shown to inhibit the oxidation of medium-chain-length acyl carnitines specifically: the oxidation of palmitoyl-carnitine was unaffected. It is suggested then that after administration of DEH P to the rat metabolite VI produces a primary lesion in the mitochondria which leads to an accumulation of lipid within the hepatocyte and that this lipid triggers the proliferation of peroxisomes. The role of increased lipid is supported by the observation that high-fat diets lead to hepatic peroxisome proliferation in rodents (Ishii et al., 1980).