Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation.
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.
van der Deure
Wendy M
WM
Department of Internal Medicine, Erasmus University Medical Center, Room Ee 502, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Hansen
Pia Skov
PS
Peeters
Robin P
RP
Kyvik
Kirsten Ohm
KO
Friesema
Edith C H
EC
Hegedüs
Laszlo
L
Visser
Theo J
TJ
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D003718:Denmark; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007457:Iodine Radioisotopes; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013431:Sulfates; D013974:Thyroxine / Q000097:blood / Q000378:metabolism*; D014162:Transfection; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism*; D014427:Twins
D007457:Iodine Radioisotopes; D027361:Organic Anion Transporters; C473187:SLCO1C1 protein, human; D013431:Sulfates; D014284:Triiodothyronine; D013974:Thyroxine