Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine

Thyroid hormone transporters are responsible for the cellular uptake of thyroid hormones, which is a prerequisite for their subsequent metabolism and action at nuclear thyroid hormone receptors. A recently discovered thyroid hormone derivative, 3-iodothyronamine (T 1AM), has distinct biological effects that are opposite those of thyroid hormone. Here we investigate the effects of T 1AM on thyroid hormone transporters using COS-1 cells transfected with the multispecific organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 1C1, as well as the specific thyroid hormone transporters MCT8 and MCT10, and show that T 1AM displays differential inhibition of T 3 and T 4 cellular uptake by these transporters. T 1AM inhibits T 3 and T 4 transport by OATP1A2 with IC 50 values of 0.27 and 2.1 μM, respectively. T 4 transport by OATP1C1, which is thought to play a key role in thyroid hormone transport across the blood-brain barrier, is inhibited by T 1AM with an IC 50 of 4.8 μM. T 1AM also inhibits both T 3 and T 4 uptake via MCT8, the most specific thyroid hormone transporter identified to date, with IC 50 values of 95 and 31 μM, respectively. By contrast, T 1AM has no effect on thyroid hormone transport by OATP1B3 and MCT10. Given that OATP1A2, OATP1C1, and MCT8 are all present in the brain, T 1AM may play an important role in modulating thyroid hormone delivery and activity in specific target regions in the central nervous system.

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