MECHANISM OF DI(2-ETHYLHEXYL)PHTHALATE HEPATOTOXICITY

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In a 2-year study conducted by the National Toxicology Program, the industrial plasticizer, d1 (2-ethylhexyl) phthalate (DEHP), was found to be carcinogenic to the liver of F344 rats and B6C3Ff1 mice. Because DEHP induces peroxisome proliferation, but is not itself a mutagen. It has been suggested that the carcinogenicity of this chemical may be due to excessive peroxisomal production of hydrogen peroxide. Peroxisomal enzyme activities were also found to increase in primary hepatocyte cultures incubated with mono (2-ethylhexyl) phthalate (the primary metabolite of DEHP), and with nafenopin or clofibric acid, two hypolipidemic drugs which are potent peroxisome proliferators in rats. Conjugated dienes, an indicator of lipid peroxidation, were also found to increase in concentration in hepatocytes incubated with peroxisome proliferators. The latter increases were sensitive to the antioxidant, N,N'-diphenyl-p- phenylenediamine (DPPD). Furthermore, the extent of peroxisome proliferation by nafenopin was increased in the presence of DPPD. Thus, oxidative stress was associated with peroxisome proliferation in rodent hepatocytes.