Interactions between human plasma sex hormone-binding globulin and xenobiotic ligands

Human sex hormone-binding globulin (SHBG) binds sex steroids with high affi nity. In plasma, the: number of SHBG steroid-binding sites far exceeds the molar concentrations of sex steroids, and will accommodate other ligands su ch as phytoestrogens and fatty acids. We have therefore developed a screeni ng assay to identify ligands for SHBG, which exist in our diet or environme nt. This assay allows the binding of potential ligands to SHBG to be assess ed under physiological conditions, and is sensitive to the effects of plasm a constituents. Several classes of endocrine active compounds were tested, including hydroxy-polychlorinated biphenyls (HO-PCBs), phthalate esters, mo noesters, chlorinated pesticides, as well as synthetic estrogens and phytoe strogens. The relative binding affinities (RBAs) of various compounds to SH BG were determined in competitive displacement assays, by comparison with 1 7 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 th ese include: several phytoestrogens, such as genistein and kaempferol, poly chlorinated biphenyls, phthalate esters and monoesters. Of nine HO-PCB cong eners tested only 4-OH-2', 3', 4', 5'-tetraCB and 4-OH-2, 2', 3', 4', 5'-pe ntaCB bound SHBG in undiluted serum with RBAs of 0.05 and 0.11. Although al l 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 lo w, such as in pre-pubertal children and women taking oral contraceptives. ( C) 2001 Elsevier Science Ltd. All rights reserved.