MECHANISM OF DI(2-ETHYLHEXYL)PHTHALATE HEPATOTOXICITY

在国家毒理学计划进行的一项为期两年的研究中， 工业增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）被发现， 对F344大鼠和B6 C3 Ff 1小鼠的肝脏具有致癌性。因为DEHP 诱导过氧化物酶体增殖，但本身不是诱变剂。它有 有人认为，这种化学物质的致癌性可能是由于 过氧化物酶体产生过多的过氧化氢。过氧化物酶体酶 在原代肝细胞培养物中， 与邻苯二甲酸单（2-乙基己基）酯（ DEHP），并与萘芬诺平或氯贝酸，两种降血脂药物 它们是大鼠体内有效的过氧化物酶体增殖剂。共轭二烯 脂质过氧化指标，也被发现增加， 与过氧化物酶体增殖剂孵育的肝细胞中的浓度。的 后者的增加是敏感的抗氧化剂，N，N '-二苯基-p- 苯二胺（DPPD）。此外，过氧化物酶体的程度 在DPPD的存在下，萘诺平的增殖增加。因此，在本发明中， 氧化应激与啮齿类动物过氧化物酶体增殖有关 肝细胞

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.