MECHANISM OF DI(2-ETHYLHEXYL)PHTHALATE HEPATOTOXICITY

点击翻译按钮获取中文摘要

In a two-year study conducted by the National Toxicology Program, the industrial plasticizer, di(2-ethylhexyl)phthalate (DEHP), was found to be hepatocarcinogenic in B6C3F1 mice and F344 rats. Since DEHP induces peroxisome proliferation but is not itself a mutagen, it has been suggested that carcinogenicity of this chemical may be due excessive peroxisomal production of H202. The effects of DEHP on hepatic peroxisomes in rats and mice have been investigated. Peroxisomal acyl CoA oxidase, the first enzyme in the beta-oxidation sequence, was established as the most suitable marker for hepatic peroxisome proliferation. Maximal peroxisomal induction by DEHP occurred at a dose of 2 g/kg/day, and the no-observable effect dose was 0.6 g/kg/day. Kinetic data on the rates of formation of H202 during peroxisomal oxidation of palmitoyl CoA, and of degradation of H202 by catalase were used to estimate in vitro steady state H202 concentrations during peroxisomal beta-oxidation. Increases in steady state (H202) in liver homogenates of rats treated with DEHP and other peroxisome proliferators (nafenopin and di(2- ethylhexyl) phthalate) correlated well with the carcinogenic potential of these chemicals. These findings are consistent with an involvement of peroxisome proliferation in hepatocarcinogenesis. Peroxisomal enzymes activities were also found to increase in primary hepatocyte cultures incubated with mono(2-ethylhexyl) phthalate (the primary metabolite of DEHP), nafenopin, and clofibric acid. Furthermore, there was an increase in conjugated dienes, an indicator of lipid peroxidation, in treated hepatocytes. Thus, oxidative stress was associated with peroxisome proliferation in rodent hepatocytes.