MECHANISM OF DI(2-ETHYLHEXYL)PHTHALATE HEPATOTOXICITY

在国家毒理学研究所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-乙基己酯) (DEHP)，在B6C3F1小鼠中被发现是肝癌的致癌物，并且 F344只大鼠。由于DEHP诱导了过氧化物酶的增殖，但 本身并不是一种诱变剂，有研究表明， 这种化学物质可能是由于过多的过氧化物体产生 H202。DEHP对大鼠肝组织过氧化脂质的影响 已经对老鼠进行了研究。过氧化物酰基辅酶A氧化酶 β-氧化序列中的第一种酶被确定为 是肝过氧化物酶增殖体最合适的标志物。 DEHP诱导过氧化体的最大剂量为2 无明显作用剂量为0.6g/kg/d。 过氧化体过程中H_202形成速率的动力学数据 棕榈酰辅酶A的氧化和H202的降解 过氧化氢酶用于估计体外稳态H202 过氧化物酶-β氧化过程中的浓度。增加了 大鼠肝匀浆稳态(H_(202)) DEHP和其他过氧化物酶体增殖剂(奈非诺平和二(2- 邻苯二甲酸乙基己酯)与致癌物质有很好的相关性 这些化学物质的潜力。这些发现与 过氧化物酶增殖体参与了血管内皮细胞的增殖 肝癌的发生。过氧化物酶活性也 在原代肝细胞培养中发现与 邻苯二甲酸单(2-乙基己基)酯(DEHP的主要代谢物)， 奈非诺平和氯非匹酸。此外，还出现了增长 在共轭双烯中，脂质过氧化的指示物，在治疗中 肝细胞。因此，氧化应激与 啮齿动物肝细胞中的过氧化物酶体增殖。

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.