MECHANISM OF DI(2-ETHYLHEXYL)PHTHALATE HEPATOTOXICITY

邻苯二甲酸二(2-乙基己基)酯的肝毒性机制

• 批准号: 3941487
• 负责人: R L MELNICK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3941487
• 关键词: acetyl coA; catalase; chemical carcinogenesis; diethylhexylphthalate; free radicals; glutathione peroxidase; hepatotoxin; hydrogen peroxide; lipid peroxides; liver neoplasms; peroxidation; peroxisome; superoxide dismutase; superoxides; toxicant interaction

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.

在一项由国家毒理学委员会进行的为期两年的研究中， 程序，工业增塑剂，邻苯二甲酸二（2-乙基己基）酯 在B6 C3 F1小鼠中发现DEHP具有致癌性， F344大鼠。 由于DEHP可诱导过氧化物酶体增殖， 它本身不是诱变剂，但已表明， 这种化学物质可能是由于过量的过氧化物酶体产生， H202 DEHP对大鼠肝脏过氧化物酶体的影响 老鼠已经被研究过了。 过氧化物酶体酰基辅酶A氧化酶 β-氧化序列中的第一个酶，被确定为 是肝过氧化物酶体增殖的最合适的标志物。 DEHP的最大过氧化物酶体诱导发生在剂量为2 g/kg/天，无明显作用剂量为0.6 g/kg/天。 过氧化物酶体过程中H2 O2形成速率的动力学数据 棕榈酰辅酶A的氧化和H2 O2的降解， 过氧化氢酶用于估计体外稳态H2 O2 过氧化物酶体β-氧化期间的浓度。 增加 稳态（H2 O2）在用 DEHP和其他过氧化物酶体增殖剂（萘芬诺平和二（2- 邻苯二甲酸乙基己酯）与致癌物质 这些化学品的潜力。 这些研究结果是一致 过氧化物酶体增殖参与 肝癌发生 过氧化物酶体酶活性也 发现在孵育的原代肝细胞培养物中增加 邻苯二甲酸单（2-乙基己基）酯（DEHP的主要代谢产物）， 萘诺平和氯贝酸。 此外， 在共轭二烯中，脂质过氧化的指标，在处理过的 肝细胞 因此，氧化应激与 啮齿类动物肝细胞中的过氧化物酶体增殖。