Hodgert Jury H, Zacharewski T R, Hammond G L
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ont., Canada.
J Steroid Biochem Mol Biol. 2000 Dec 15;75(2-3):167-76. doi: 10.1016/s0960-0760(00)00168-0.
Human sex hormone-binding globulin (SHBG) binds sex steroids with high affinity. In plasma, the number of SHBG steroid-binding sites far exceeds the molar concentrations of sex steroids, and will accommodate other ligands such as phytoestrogens and fatty acids. We have therefore developed a screening assay to identify ligands for SHBG, which exist in our diet or environment. This assay allows the binding of potential ligands to SHBG to be assessed under physiological conditions, and is sensitive to the effects of plasma constituents. Several classes of endocrine active compounds were tested, including hydroxy-polychlorinated biphenyls (HO-PCBs), phthalate esters, monoesters, chlorinated pesticides, as well as synthetic estrogens and phytoestrogens. The relative binding affinities (RBAs) of various compounds to SHBG were determined in competitive displacement assays, by comparison with 17 beta-estradiol (RBA=100). Synthetic estrogens bound SHBG with RBAs of 0.4 (ethinylestradiol)-0.2 (diethylstilbestrol), while some phytoestrogens bound with RBAs of 0.12 (coumestrol)-0.04 (naringenin). Many compounds did not bind to SHBG with sufficient affinity to allow RBA measurements, and these include: several phytoestrogens, such as genistein and kaempferol, polychlorinated biphenyls, phthalate esters and monoesters. Of nine HO-PCB congeners tested only 4-OH-2', 3', 4', 5'-tetraCB and 4-OH-2, 2', 3', 4', 5'-pentaCB bound SHBG in undiluted serum with RBAs of 0.05 and 0.11. Although all test compounds bound to SHBG with much lower affinity than endogenous sex steroids, these interactions may be physiologically relevant in situations where plasma SHBG levels are high and endogenous sex steroid levels are low, such as in pre-pubertal children and women taking oral contraceptives.
人类性激素结合球蛋白（SHBG）能以高亲和力结合性类固醇。在血浆中，SHBG类固醇结合位点的数量远远超过性类固醇的摩尔浓度，并且还能容纳其他配体，如植物雌激素和脂肪酸。因此，我们开发了一种筛选试验，以识别存在于我们饮食或环境中的SHBG配体。该试验能在生理条件下评估潜在配体与SHBG的结合情况，并且对血浆成分的影响敏感。我们测试了几类内分泌活性化合物，包括羟基多氯联苯（HO-PCBs）、邻苯二甲酸酯、单酯、氯代农药，以及合成雌激素和植物雌激素。通过与17β-雌二醇（相对结合亲和力[RBA]=100）比较，在竞争性置换试验中测定了各种化合物与SHBG的相对结合亲和力。合成雌激素与SHBG结合的RBA为0.4（炔雌醇）-0.2（己烯雌酚），而一些植物雌激素与SHBG结合的RBA为0.12（香豆雌酚）-0.04（柚皮素）。许多化合物与SHBG的结合亲和力不足，无法进行RBA测量，这些化合物包括：几种植物雌激素，如染料木黄酮和山奈酚、多氯联苯、邻苯二甲酸酯和单酯。在所测试的9种HO-PCB同系物中，只有4-OH-2',3',4',5'-四氯联苯和4-OH-2,2',3',4',5'-五氯联苯在未稀释血清中与SHBG结合，RBA分别为0.05和0.11。尽管所有测试化合物与SHBG的结合亲和力都远低于内源性性类固醇，但在血浆SHBG水平高而内源性性类固醇水平低的情况下，如青春期前儿童和服用口服避孕药的女性，这些相互作用可能具有生理相关性。
