Assessing the role of ortho-substitution on polychlorinated biphenyl binding to transthyretin, a thyroxine transport protein

ortho-Substituted polychlorinated biphenyls (PCBs) make up a large part of the PCB residue found in the environment and human tissues. Our laboratory as well as others have demonstrated that ortho-substituted congeners exhibi t important biological activities by aryl hydrocarbon (Ah) receptor-indepen dent mechanisms, including changes in second messenger systems necessary fo r normal cell function and growth. Previous structure-activity relationship (SAR) studies on second messengers and transthyretin (TTR; prealbumin) bin ding focused little attention on the ortho-substituted PCBs. Disruption of thyroid hormone (TH) transport is one potentially important mechanism by wh ich PCBs can alter TH homeostasis. A more systematic study of PCB binding t o TTR, a major TH transport protein, was undertaken, in which the role of o rtho-substitution was more thoroughly investigated. Results from this study indicated that the ortho-only substituted series showed significant bindin g activity and the relative affinities were 2,2',6 > 2,2' = 2,6 >> 2 = 2,2' ,6,6'. As anticipated on the basis of steric considerations, bromine was sh own to be more active as an ortho-substituent where the relative affinity o f 2,2'-Br was equivalent to 2,2',6-Cl. The congener patterns (dimeta-substi tution in one or both rings) most closely resembling the diiodophenolic rin g of thyroxine (T-4) showed the highest binding activity. Multiple ortho-su bstituents were shown to decrease binding activity in such patterns, Congen er patterns (single meta-substitution in one or both rings) more closely re sembling the monoiodophenolic ring of T-3 showed significantly lower bindin g activity, consistent with the relatively low binding activity of T-3 and smaller size of chlorine compared to iodine. The addition of ortho-substitu tion to such patterns gave variable results depending on the substituent re lationship (adjacency or nonadjacency) to the pattern. Some patterns such a s 2,2',4,4',5,5' showed good binding activity and represent common congener s in the commercial Aroclor mixtures and in the environment. The binding po tencies of ortho-PCBs to TTR may represent: a signature SAR that predicts s pecific biologic/toxic effects. Tn this regard, the binding potencies were consistent with measured biological activities of these PCBs, including eff ects on cell dopamine content. Ca2+ homeostasis, and protein kinase C trans location in neuronal cells and brain homogenate preparations. (C) 2000 Acad emic Press.