Membrane transporters for thyroid hormone

Abstract

Purpose of reviewAction and metabolism of thyroid hormones are intracellular events, which require their uptake across the plasma membrane. Cellular uptake of thyroid hormone is mediated by transporters, and recently, some of these transporters have been identified at the molecular level. Here we review the biochemistry, molecular biology, and clinical relevance of these transporters. Recent findingsIodothyronine transporters have been identified among the members of different transporter families, including Na/taurocholate cotransporting polypeptide, different (Na-independent) organic anion transporting polypeptides, the L-type amino acid transporters, and monocarboxylate transporter-8. Two transporters are particularly interesting: organic anion transporting polypeptide-1C1, which shows a high affinity for T4 and T3 and is almost exclusively expressed in brain, and monocarboxylate transporter-8, which is a very active iodothyronine transporter with a slight preference for T3 and is abundantly expressed in different tissues, including brain. Organic anion transporting polypeptide-1C1 is probably important for T4 transport across the blood--brain barrier and that monocarboxylate transporter-8 for T3 uptake in neurons. Recently, mutations in MCT8, which is located on the X chromosome, were identified in male patients with severe psychomotor retardation and elevated serum levels of T3. Summary Recent studies have greatly increased our knowledge about the identity of thyroid hormone transporters and in particular their physiologic relevance. The dramatic consequences of mutations in monocarboxylate transporter-8 represent a novel mechanism of thyroid hormone resistance due to inhibited cellular entry of the hormone.

The role of the placenta in thyroid hormone delivery to the fetus

“…32 The importance of THTs during development has been realized following the discovery of various novel mutations in SLC16A2-which encodes the THT protein monocarboxylate transporter 8 (MCT8, also known as MOT8)-in individuals with severe global neurological impairment accompanied by high free T 3 but decreased free T 4 levels. 33,34 Although it has been assumed that this phenotype is primarily due to defective thyroid hormone uptake by neurons within the CNS, 35 the possibility that impaired thyroid hormone transport across the placenta might contribute to this pathology also has to be considered.…”

Modeling Kinetics of Subcellular Disposition of Chemicals

“…(1067) This route has been considered a possible mechanism for the increase in bioavailability of the drugs bearing, at least in some parts, some similarity to the nutrient molecules such as antiviral nucleosides(1065) and peptidomimetic drugs including β-lactam antibiotics and inhibitors of angiotensin converting enzyme, renin, and thrombin. (1068)…”

“…Protein carrier systems have evolved in all organisms for the uptake of sugars, 1060 – 1062 amino acids, dipeptides and tripeptides, 1063 , 1064 nucleosides,( 1065 ) lipids,( 1062 ) vitamins, 1062 , 1066 and hormones in higher organisms. ( 1067 ) This route has been considered a possible mechanism for the increase in bioavailability of the drugs bearing, at least in some parts, some similarity to the nutrient molecules such as antiviral nucleosides( 1065 ) and peptidomimetic drugs including β-lactam antibiotics and inhibitors of angiotensin converting enzyme, renin, and thrombin. ( 1068 )…”