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Thyroid Hormone Transport and Metabolism by Organic Anion Transporter 1C1 and Consequences of Genetic Variation

Department of Internal Medicine (W.M.v.d.D., R.P.P., E.C.H.F., T.J.V.), Erasmus University Medical Center, and Institute of Regional Health Research (O.K.), 3015-GE Rotterdam, The Netherlands; Department of Endocrinology and Metabolism (S.H., L.H.), Odense University Hospital, DK-5000 Odense, Denmark; and The Danish Twin Registry (S.H., O.K.), Epidemiology, Institute of Public Health, University of Southern Denmark, DK-5230 Odense, Denmark

Address all correspondence and requests for reprints to: Theo J. Visser, Ph.D., Department of Internal Medicine, Erasmus University Medical Center, Room Ee 502, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: t.j.visser{at}erasmusmc.nl.

Organic anion transporting polypeptide (OATP) 1C1 has been characterized as a specific thyroid hormone transporter. Based on its expression in capillaries in different brain regions, OATP1C1 is thought to play a key role in transporting thyroid hormone across the blood-brain barrier. For this reason, we studied the specificity of iodothyronine transport by OATP1C1 in detail by analysis of thyroid hormone uptake in OATP1C1-transfected COS1 cells. Furthermore, we examined whether OATP1C1 is rate limiting in subsequent thyroid hormone metabolism in cells cotransfected with deiodinases. We also studied the effect of genetic variation in the OATP1C1 gene: polymorphisms were determined in 155 blood donors and 1192 Danish twins and related to serum thyroid hormone levels. In vitro effects of the polymorphisms were analyzed in cells transfected with the variants. Cells transfected with OATP1C1 showed increased transport of T₄ and T₄ sulfate (T4S), little transport of rT₃, and no transport of T₃ or T₃ sulphate, compared with mock transfected cells. Metabolism of T₄, T4S, and rT₃ by cotransfected deiodinases was greatly augmented in the presence of OATP1C1. The OATP1C1-intron3C>T, Pro143Thr, and C3035T polymorphisms were not consistently associated with thyroid hormone levels, nor did they affect transport function in vitro. In conclusion, OATP1C1 mediates transport of T₄, T4S, and rT₃ and increases the access of these substrates to the intracellular active sites of the deiodinases. No effect of genetic variation on the function of OATP1C1 was observed.