title: Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine.
abstract: 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(1)AM), has distinct biological effects that are opposite those of thyroid hormone. Here we investigate the effects of T(1)AM 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(1)AM displays differential inhibition of T(3) and T(4) cellular uptake by these transporters. T(1)AM inhibits T(3) and T(4) transport by OATP1A2 with IC(50) values of 0.27 and 2.1 microM, 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(1)AM with an IC(50) of 4.8 microM. T(1)AM 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 microM, respectively. By contrast, T(1)AM has no effect on thyroid hormone transport by OATP1B3 and MCT10. Given that OATP1A2, OATP1C1, and MCT8 are all present in the brain, T(1)AM may play an important role in modulating thyroid hormone delivery and activity in specific target regions in the central nervous system.
authors.affiliation: Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Ianculescu
authors.forename: Edith C H
authors.initials: EC
authors.lastname: Friesema
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D027981:Symporters; D013963:Thyroid Hormones / Q000378:metabolism* / Q000493:pharmacokinetics; D013970:Thyronines / Q000494:pharmacology*; D014162:Transfection
chemical_list: C487948:3-iodothyronamine; D026921:Amino Acid Transport Systems, Neutral; D027501:Monocarboxylic Acid Transporters; D027361:Organic Anion Transporters; C498964:SLC16A10 protein, human; C090735:SLC16A2 protein, human; C512988:SLCO1A2 protein, human; C473187:SLCO1C1 protein, human; D027981:Symporters; D013963:Thyroid Hormones; D013970:Thyronines