Abstract
As a prerequisite for intracellular processes like deiodination, sulfoconjugation or binding to the thyroid hormone (TH) receptor, TH is actively transported across the cell membrane by TH transporters. Several proteins can facilitate this transport, such as members of the organic anion transporting polypeptide family (OATPs), amino acid transporters or monocarboxylate transporters. We have previously demonstrated that OATP1B1 strongly induces uptake of iodothyronine sulfates T4 sulfate (T4S), T3 sulfate (T3S) and rT3 sulfate (rT3S), but has no T4 and T3 and only little rT3 transport activity. A different member of the OATP1 subfamily, OATP1C1, transports T4, T4S and rT3. In this study, we examined the specificity of iodothyronine transport by the two remaining human members of the OATP1 subfamily, OATP1A2 and OATP1B3, by analysis of TH uptake and metabolism in transfected COS1 cells. Compared to mock transfected cells OATP1A2 significantly induced uptake of T4, T3, rT3, T4S, T3S and rT3S. In addition, metabolism of these substrates by co-transfected deiodinases was greatly augmented in the presence of OATP1A2. In contrast to OATP1A2, OATP1B3 did not facilitate T4 transport and only to some extent T3 uptake. However, transport of rT3 and iodothyronine sulfates was clearly induced by OATP1B3. In addition, metabolism of these substrates by D1 was markedly increased when cells were co-transfected with OATP1B3. In conclusion, all four human members of the OATP1 subfamily facilitate uptake of (sulfated) iodothyronines and are rate-limiting in subsequent metabolism by deiodinases. Interestingly, OATP1B1 and OATP1B3, both expressed exclusively in the liver, only transport rT3 and iodothyronine sulfates, probably facilitating their degradation by liver D1. Brain-specific OATP1C1 shows transport of T4, T4S and rT3, whereas OATP1A2, which is expressed in liver, kidney and at the blood brain barrier, shows transport of all iodothyronines and their sulfates.