title: The effect of the plasticizers TBEP (tris-(2-butoxyethyl)-phosphate) and DEHP (di-(2-ethylhexyl)-phthalate) on beta-adrenergic ligand binding to alpha 1-acid glycoprotein and mononuclear leukocytes.
abstract: The plasticizers tris-(2-butoxyethyl)-phosphate (TBEP) and di-(2-ethylhexyl)-phthalate (DEHP) and the beta-adrenergic receptor-blockers [3H]-(-)-dihydroalprenolol ([3H]-(-)-DHA) and [3H]-(-)-CGP 12177 were tested for their ability to interact with beta-adrenergic binding to alpha 1-acid glycoprotein (AAG) and mononuclear leukocytes (MNL). The IC50-values, obtained by displacement of [3H]-(-)-DHA bound to AAG, were 3.5 nM, 2 microM and 4 microM for TBEP, (-)-alprenolol and DEHP, respectively. (+/-)-CGP 12177 had virtually no effect on radioligand binding to AAG. The [3H]-(-)-CGP 12177 binding to MNL consisted of beta-adrenergic receptor binding (Kd = 210 pM) and non-saturable binding. [3H]-(-)-DHA was bound to two different classes of binding sites on MNL, the beta-adrenergic receptors (Kd = 440 pM) and a secondary class of binding sites (Kd = 64 nM). (+/-)-CGP 12177 displaced about 30% of [3H]-(-)-DHA from MNL with an IC50-value of 190 pm. (-)-ALP displaced about 85% of total bound radioligand and gave a biphasic displacement curve with IC50-values of 320 pM and 690 mM, respectively. TBEP displaced a considerable fraction of [3H]-(-)-CGP 12177 and [3H]-(-)-DHA bound to MNL beta-adrenergic receptors, whereas DEHP had no effect. In contrast, DEHP caused displacement of [3H]-(-)-DHA from the MNL low affinity sites, but was a markedly less potent displacer compared to TBEP. The present study shows that TBEP and DEHP interact with beta-adrenergic transport proteins, non-specific tissue binding sites and beta-adrenergic receptors coupled to adenylate cyclase. Plasticizers may thus affect the biology and pharmacology of the beta-adrenergic signal system.
authors.affiliation: Department of Pharmacology, University of Tromsø, Norway.
authors.forename: G
authors.initials: G
authors.lastname: Sager
authors.forename: C
authors.initials: C
authors.lastname: Little
mesh_terms: D000328:Adult; D001667:Binding, Competitive; D004051:Diethylhexyl Phthalate / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D009961:Orosomucoid / Q000187:drug effects* / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D010968:Plasticizers / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism
chemical_list: D009943:Organophosphorus Compounds; D009961:Orosomucoid; D010795:Phthalic Acids; D010968:Plasticizers; D011943:Receptors, Adrenergic, beta; D004051:Diethylhexyl Phthalate; C013320:tris(2-butoxyethyl) phosphate