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: 3965211
• 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/3965211
• 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 toxicology/carcinogenicity study conducted by the National Toxicology Program, di(2-ethylhexyl)phthalate (DEHP) was found to be hepatocarcinogenic in B6C3F1 mice and F334 rats. Since DEHP also causes peroxisome proliferation, it has been suggsted that the carcinogenicity of this chemical may be related to excessive peroxisomal production of H202. It is the objective of this project to examine the changes in H2O2 concentrations resulting from peroxisomal fatty acyl-CoA oxidation and catalase activity in livers of rats and mice treated with DEHP. Further assessment of an involvement of ractive intermediates of oxygen reduction in DEHP induced hepatotoxicity will be made from measurements of (a) activities of enzymes that eliminate toxic oxygen products (catalase, superoxide dismutase, glutathione peroxidase), (b) lipid peroxidation, and (c) superoxide anion radical production. New studies have begun to characterize the chemical requirements for induction of peroxisome proliferation in isolated rat hepatocytes.

在一项为期两年的毒理学/致癌性研究中， 国家毒理学计划，邻苯二甲酸二（2-乙基己基）酯 在B6 C3 F1小鼠中发现DEHP具有肝癌致癌性， F334大鼠。 由于DEHP也会导致过氧化物酶体增殖， 已经证实这种化学物质的致癌性 可能与H2 O2的过量过氧化物酶体产生有关。 本项目的目的是研究 过氧化物酶体脂肪酰辅酶A导致的H2 O2浓度 大鼠和小鼠肝脏中的氧化和过氧化氢酶活性 用DEHP处理。 对参与的进一步评估 DEHP诱导的氧还原反应性中间体 肝毒性将通过测量（a） 消除有毒氧产物的酶的活性 （过氧化氢酶、超氧化物歧化酶、谷胱甘肽过氧化物酶），（B） 脂质过氧化和（c）超氧阴离子自由基 生产 新的研究已经开始描述 过氧化物酶体诱导的化学要求 在分离的大鼠肝细胞中增殖。