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: 3918627
• 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/3918627
• 关键词: acetyl coA; catalase; chemical carcinogenesis; diethylhexylphthalate; enzyme mechanism; free radicals; glutathione peroxidase; hepatotoxin; hydrogen peroxide; laboratory mouse; laboratory rat; 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 to 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 B-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 H2O2 during peroxismal oxidation of palmitoyl CoA, and of degradation of H2O2 by catalase were used to estimate in vitro steady state H2O2 concentrations during peroxisomal beta- oxidation. Increases in steady state (H2O2) 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. Studies have been initiated to characterize hydrogen peroxide mediated lipid peroxidation in isolated hepatocytes.

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）， 在B6 C3 F1小鼠和F344大鼠中发现了肝癌。 以来 DEHP诱导过氧化物酶体增殖，但本身不是诱变剂， 有人认为，这种化学物质的致癌性可能是 由于H2 O2的过氧化物酶体产生过多。 的影响 DEHP对大鼠和小鼠肝脏过氧化物酶体的影响 研究了 过氧化物酶体酰基辅酶A氧化酶，第一个酶， B-氧化顺序为最佳氧化顺序 肝过氧化物酶体增殖的标志物。 最大过氧化物酶体 DEHP的诱导发生在2 g/kg/天的剂量下， 可观察到的作用剂量为0.6 g/kg/天。 速率的动力学数据 棕榈酰辅酶A的过氧化物酶氧化过程中H2 O2的形成， 和过氧化氢酶降解H_2O_2的能力， 过氧化物酶体β- 氧化 肝匀浆中稳态（H2 O2）增加 用DEHP和其他过氧化物酶体增殖剂处理的大鼠 （萘诺平和邻苯二甲酸二（2-乙基己基）酯）与 这些化学物质的致癌潜力。 这些发现 与过氧化物酶体增殖的参与一致， 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，脂质过氧化的指示剂， 处理的肝细胞。 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。 研究已经 开始表征过氧化氢介导的脂质 在分离的肝细胞中的过氧化。