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: 3898088
• 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/3898088
• 关键词: acetyl coA; aniline; antihyperlipoproteinemic agent; catalase; chemical carcinogenesis; clofibrate; diethylhexylphthalate; enzyme mechanism; free radicals; glutathione peroxidase; hepatotoxin; hydrogen peroxide; laboratory mouse; laboratory rat; lipid peroxides; liver neoplasms; peroxidation; peroxisome; superoxide dismutase; superoxides; tissue /cell culture; toxicant interaction; toxin metabolism

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.

在国家毒理学项目进行的一项为期两年的研究中， 工业增塑剂邻苯二甲酸二异辛酯(DEHP)被发现 对F344大鼠和B6C3Ff1小鼠的肝脏有致癌作用。因为DEHP 诱导过氧化酶体增殖，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 过氧化氢产生过多的过氧化物体。过氧化物酶 在原代肝细胞培养中也发现活性增加。 与邻苯二甲酸单(2-乙基己基)酯(主要代谢物 DEHP)，以及与那非诺平或氯非比酸联合使用的两种降血脂药物 它们是大鼠体内有效的过氧化物酶增殖物。共轭双烯，一种 脂质过氧化的指示剂，也被发现在 用过氧化物酶增殖物孵育的肝细胞的浓度。这个 后者的增加对抗氧化剂N，N‘-二苯基-p-... 苯二胺(DPPD)。此外，过氧化物体的程度 在DPPD存在的情况下，奈非诺平的增殖作用增强。因此， 氧化应激与啮齿动物体内过氧化物酶的增殖有关 肝细胞。