Metabolic activation of endocrine-disruptors in animal body

动物体内内分泌干扰物的代谢激活

• 批准号: 13672343
• 负责人: KITAMURA Shigeyuki
• 金额: $ 2.24万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672343/
• 关键词: Estrogen; Antiandrogen; Thyroid hormonal compound; Vitellogenin; Endocrine disruptor; Drug metabolizing enzyme; Metabolic activation; Environmental pollutant; 内分泌撹乱前駆物質; 甲状腺ホルモン撹乱物質

The metabolic activation of endocrine disrupters was examined in this study.1. Estrogenic activity was estimated by the reporter assay using human breast cancer cell line MCF-7. We found some proestrogens which were not estrogenic and produced their activities after the incubation with liver microsomes in the presence of NADPH. As proestrogens, we detected 2-nitrofluorene, trans-stilbene, biphenyl, diphenylmethane, dibenzyl, 2, 2-diphenylpropane, benzylideneacetone, styrene oligomers, diphenylamine, diphenylsulfone, azobenzene, pyrene, permethrin, dimethylphthalate and chalchone by screening the estrogenic activities of their metabolites. These proestrogens were converted to their hydroxylated active metabolites in vivo and in vitro in rats. The hydroxylation was mediated by liver microsomal cytochrome P450 2B1 or 1A1. 2. Bisphenol A, fluorene, pyrene, DDTs and some organophosphorus insecticides exhibited antiandrogenic activity. Fenthion sulfoxide also exhibited the activity after incubation with rat liver preparations. 3. Tetrabromobisphenol A, a flame retardant, exhibited thyroid hormonal activity. Some PCBs also exhibited the activity after the hydroxylation by cytochrome P450 system. 4. Trans-Stilbene, 2-nitrofluorene and fenthion showed endocrine-disrupting actions in vivo in rats. 5. When male goldfish were kept in the water containing trans-stilbene, diphenyl or 2-nitrofluorene (5x10^<-6> M) for five days, the vitellogenin level in blood was markedly increased. These hydroxylated compounds were detected in keeping water. These facts suggest that these proestrogens were activated to estrogens in mammals and fish.

本研究对内分泌干扰物的代谢活化进行了研究.雌激素活性通过使用人乳腺癌细胞系MCF-7的报告基因测定来估计。我们发现一些雌激素前体在NADPH存在下与肝微粒体孵育后不具有雌激素活性。作为雌激素前体，通过筛选其代谢产物的雌激素活性，检测到2-硝基芴、反式二苯乙烯、联苯、二苯甲烷、二苄基、2，2-二苯基丙烷、亚苄基丙酮、苯乙烯低聚物、二苯胺、二苯砜、偶氮苯、芘、氯菊酯、邻苯二甲酸二甲酯和查尔酮。这些前雌激素在大鼠体内和体外转化为它们的羟基化活性代谢产物。羟基化由肝微粒体细胞色素P450 2B 1或1A 1介导。2.双酚A、芴、芘、DDTs和某些有机磷杀虫剂具有抗雄激素活性。倍硫磷亚砜在与大鼠肝脏制剂孵育后也显示出活性。3.阻燃剂四溴双酚A具有甲状腺激素活性。部分多氯联苯经细胞色素P450系统羟基化后也表现出活性。4.反式二苯乙烯、2-硝基芴和倍硫磷在大鼠体内显示出内分泌干扰作用。5.雄性金鱼在含有反式二苯乙烯、联苯或2-硝基芴（5 × 10 ~（-1）M）的水中饲养<-6>5天后，血液中卵黄原蛋白水平显著升高。这些羟基化合物被检测到在保持水。这些事实表明，这些前雌激素在哺乳动物和鱼类中被激活为雌激素。

项目成果

Shigeyuki Kitamura: "Antiandrogenic Activity of the Organophosphorus Pesticide Fenthion and Related Compounds, and the Effect of Metabolism"Environmental Health Perspectives. (In press).

Shigeyuki Kitamura：“有机磷农药倍硫磷和相关化合物的抗雄激素活性以及代谢的影响”环境健康观点。

Osamu Ueda: "Deacylation of N-Arylformides and N-Arylacetamides by Formamidase in Rat Liver"Drug Metabolism and Disposition. 31(12). 1297-1299 (2002)

Osamu Ueda：“大鼠肝脏中甲酰胺酶对 N-芳基甲酰胺和 N-芳基乙酰胺的脱酰作用”药物代谢和处置。

S.Kitamura, N.Jinno, S.Ohta, H.Kuroki and N.Fujimoto: "Thyroid Hormonal Activity of the Flame Retardants Tetrabromobisphenol A and Tetrachlorobisphenol A"Biochemical and Biophysical Research Communications. 293(1). 554-559 (2002)

S.Kitamura、N.Jinno、S.Ohta、H.Kuroki 和 N.Fujimoto：“阻燃剂四溴双酚 A 和四氯双酚 A 的甲状腺激素活性”生物化学和生物物理研究通讯。

S.Kitamura, Y.Kohno, Y.Okamoto, M.Takeshita and S.Ohta: "Reductive Metabolism of α,β-Ketoalkyne, 4-Phenyl-3-butyn-2-one, by Rat Liver Preparations"Drug Metabolism and Disposition. 30(4). 414-420 (2002)

S.Kitamura、Y.Kohno、Y.Okamoto、M.Takeshita 和 S.Ohta：“大鼠肝脏制剂对 α,β-酮炔、4-苯基-3-丁炔-2-酮的还原代谢”药物代谢和处置 30(4)。

Seigo Sanoh: "Cytochrome P450 1A1/2 Mediated Metabolism of trans-Stilbene in Rats and Humans"Biological and Pharmaceutical Bulletin. 25(3). 397-400 (2002)

Seigo Sanoh：“细胞色素 P450 1A1/2 介导的大鼠和人类反式二苯乙烯代谢”生物和药物通报。