Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells
Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells
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DOI：
10.1006/taap.1998.8431
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发表时间：
1998-07-01
影响因子：
3.8
通讯作者：
Gaido, KW
中科院分区：
文献类型：
--
作者：
Maness, SC;McDonnell, DP;Gaido, KW
最近的报告提出了新的关注，我们环境中的化学品可能会通过抑制雄激素受体功能来破坏正常的生殖和发育。这种高度关注也增加了我们对方法的需求，使我们能够表征与雄激素受体的化学相互作用。在这份报告中，我们描述了一种雄激素受体测定法，利用瞬时转染人雄激素受体和雄激素反应报告人的HepG 2人肝癌细胞系，我们用这种测定法来表征与雄激素受体的几种甾体和非甾体化学品，包括滴滴涕和甲氧滴滴涕的异构体的相互作用。在不存在（用于测定激动剂活性）或存在10（-7）IM双氢睾酮（用于测定拮抗剂活性）的情况下测试化学品，在该试验中，替吉奥和双氢睾酮是同样有效的激动剂。雌二醇和孕酮显示部分激动剂/拮抗剂活性。氟氯噻嗪是一种完全激动剂，而其羟基化代谢产物羟基氟氯噻嗪在10（-6）M及以上浓度下仅部分拮抗并显示出一定的激动剂活性，o，p '-DDT、o，p'-DDE、o，p '-DDD、p，p'-DDT、p，p '-DDE和p，p'-DDD在10（-6）M以上浓度下均表现为拮抗剂，p，p '-DDE在10（-5）M浓度下也显示出一定的激动剂活性，甲氧滴滴涕只有微弱的拮抗作用，而其羟基化的代谢产物，HPTE，约10倍更有效。我们的研究结果表明，HepG 2检测是一种敏感和特异性的方法，用于检测与雄激素受体的化学相互作用。我们使用这种报告基因测定来表征与雌激素和雄激素受体的相互作用，再加上更广泛的体内研究，应该有助于确定多种类固醇受体在内分泌活性化学物质作用机制中的作用。(C)北京：科学出版社.
Recent reports have raised new concerns that chemicals in our environment may disrupt normal reproduction and development through inhibition of androgen receptor function. This heightened concern has also increased our need for methods that allow us to characterize chemical interaction with the androgen receptor. In this report we describe an androgen receptor assay that utilizes the HepG2 human hepatoma cell line transiently transfected with the human androgen receptor and an androgen-responsive reporter, We used this assay to characterize the interaction with the androgen receptor of several steroidal and nonsteroidal chemicals, including isomers of DDT and methoxychlor. Chemicals were tested either in the absence (for determining agonist activity) or presence of 10(-7) IM dihydrotestosterone (for determining antagonist activity), Testosterone and dihydrotestosterone were equally potent agonists in this assay. Estradiol and progesterone displayed partial agonist/antagonist activity. Flutamide was a complete agonist, whereas its hydroxylated metabolite, hydroxyflutamide, only partially antagonized and displayed some agonist activity at 10(-6) M and above, o,p'-DDT, o,p'-DDE, o,p'-DDD, p,p'-DDT, p,p'-DDE, and p,p'-DDD all behaved as antagonists at concentrations above 10(-6) M, p,p'-DDE also showed some agonist activity at 10(-5) M, Methoxychlor was only weakly antagonistic while its hydroxylated metabolite, HPTE, was approximately 10-fold more potent. Our results demonstrate that the HepG2 assay is a sensitive and specific method for detecting chemical interaction with the androgen receptor. This reporter gene assay, which we have used to characterize interaction with both the estrogen and androgen receptors, coupled with more extensive in vivo studies, should be useful for determining the role of multiple steroid receptors in the mechanism of action of endocrine active chemicals. (C) 1998 Academic Press.