Interactions between human plasma sex hormone-binding globulin and xenobiotic ligands.
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.
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ont., Canada.
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Hodgert Jury
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Zacharewski
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Hammond
D004785:Environmental Pollutants / Q000378:metabolism; D045166:Estradiol Congeners / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000378:metabolism; D005260:Female; D006801:Humans; D007529:Isoflavones; D007700:Kinetics; D008024:Ligands; D008297:Male; D010575:Pesticides / Q000378:metabolism; D010795:Phthalic Acids / Q000737:chemistry / Q000378:metabolism; D048789:Phytoestrogens; D028321:Plant Preparations; D010944:Plants / Q000737:chemistry; D011078:Polychlorinated Biphenyls / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*; D015262:Xenobiotics / Q000737:chemistry / Q000378:metabolism*
D004785:Environmental Pollutants; D045166:Estradiol Congeners; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D008024:Ligands; D010575:Pesticides; D010795:Phthalic Acids; D048789:Phytoestrogens; D028321:Plant Preparations; D012738:Sex Hormone-Binding Globulin; D015262:Xenobiotics; C032279:phthalic acid; D011078:Polychlorinated Biphenyls