Nimrod A C, Benson W H
Department of Pharmacology and Environmental and Community Health Research, School of Pharmacy, University of Mississippi 38677, USA.
Toxicol Appl Pharmacol. 1997 Dec;147(2):381-90. doi: 10.1006/taap.1997.8296.
In teleostean in vivo studies, the vitellogenin response to environmental estrogens is not completely predicted by mammalian literature. One possible explanation for differences is heterogeneity of the estrogen receptor (ER) structure between species. Therefore, ER from channel catfish (Ictalurus punctatus) hepatic tissue was characterized by binding affinity for several compounds. Affinity was indirectly measured as potency of the chemical for inhibiting binding of radiolabeled estradiol (E2) to specific binding sites. The order of potency among therapeutic chemicals was ethinylestradiol > unlabeled E2 = diethylstilbestrol > mestranol > tamoxifen >> testosterone. Unlabeled E2 had an IC50 of 2.2 nM. Several environmentally relevant chemicals were evaluated in a similar manner and the order of potency established was the o-demethylated metabolite of methoxychlor (MXC) > nonylphenol (NP) > chlordecone > MXC > o,p'-DDT > o,p'-DDE > beta-hexachlorocyclohexane. Demethylated MXC had an IC50 1000-fold greater than that of E2. Of the most potent inhibitors, NP appeared to be a competitive inhibitor for the same binding site as E2, while o-demethylated MXC had a more complex interaction with the receptor protein. ER from nonvitellogenic females was determined to have a Kd value of 1.0 to 1.3 nM. Because E2 has been reported to up-regulate teleostean ER, the hepatic ER population following in vivo xenobiotic exposure was assessed. NP significantly increased ER per milligram hepatic protein almost to the same extent as E2, but did not increase Kd to the same extent as E2.
在硬骨鱼的体内研究中，卵黄蛋白原对环境雌激素的反应并不能完全由哺乳动物文献预测。物种间雌激素受体（ER）结构的异质性可能是差异的一个解释。因此，通过对几种化合物的结合亲和力来表征斑点叉尾鮰（Ictalurus punctatus）肝脏组织中的ER。亲和力通过化学物质抑制放射性标记雌二醇（E2）与特异性结合位点结合的效力间接测量。治疗性化学物质的效力顺序为乙炔雌二醇＞未标记的E2 =己烯雌酚＞炔雌醇＞他莫昔芬＞＞睾酮。未标记的E2的半数抑制浓度（IC50）为2.2 nM。以类似方式评估了几种与环境相关的化学物质，确定的效力顺序为甲氧滴滴涕的邻去甲基代谢物（MXC）＞壬基酚（NP）＞十氯酮＞MXC＞邻，对'-滴滴涕＞邻，对'-滴滴滴＞β-六氯环己烷。去甲基化的MXC的IC50比E2大1000倍。在最有效的抑制剂中，NP似乎是与E2相同结合位点的竞争性抑制剂，而邻去甲基化的MXC与受体蛋白的相互作用更为复杂。未产生卵黄蛋白原的雌性的ER的解离常数（Kd）值确定为1.0至1.3 nM。由于已报道E2可上调硬骨鱼的ER，因此评估了体内接触外源化合物后肝脏中的ER数量。NP使每毫克肝脏蛋白中的ER显著增加，几乎达到与E2相同的程度，但并未使Kd增加到与E
