Aliases: AHDS, XPCT, MRX22, DXS128, DXS128E, MCT7
Gene name: Solute Carrier Family 16, Member 2 (SLC16A2)
MCT8 is a member of the MCT family within the solute carrier transporter superfamily. Although the gene location and structure of MCT8 were described in 1994, the role of the encoded protein was not revealed until 2003. MCT8 is an integral membrane protein with 12 putative transmembrane domains (TMD). It facilitates the uptake and efflux of thyroid hormones (THs), with the highest affinity and specificity toward triiodothyronine (T3) and thyroxine (T4) with a Km of 4 and 8 µM, respectively. Apart from MCT8, the MCT family comprises 13 other members responsible for the transport of endogenous compounds like short chain monocarboxylates, hydrophobic monocarboxylates, THs, carnitine, creatinine, and aromatic amino acids. Based on the current knowledge, MCT8 is only responsible for the basolateral transport of THs. MCT8 is widely expressed in human tissues and seems to be of major importance in the brain, as well as in the placenta for fetal development. THs are essential for the regulation of a wide range of genes responsible for a plethora of processes such as growth, nerve differentiation, and metabolic regulation in mammals. Allan-Herndon-Dudley syndrome (AHDS) is related to deleterious mutations in the MCT8 gene. The syndrome is marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Tyrosine kinase inhibitors (TKI) used in cancer treatment such as sunitinib, sorafenib, imatinib etc. also inhibit T3 uptake via MCT8 probably by a non-competitive mechanism. The current guidelines from FDA and EMA do not contain recommendations on in vitro testing of MCT8 inhibition for NCEs.
MCT8 has a wide tissue distribution, being expressed predominantly in neurons of the cerebral and cerebellar cortexes, hippocampus, striatum, and hypothalamus , as well as at the blood-brain barrier (BBB), but also in the placenta, heart, lung, liver, thyroid, pituitary, and kidney [2-7]. In epithelial cells it is localized to the basolateral membrane.
Function, physiology, and clinically significant polymorphisms
The gene of MCT8, located at Xq13.2, is subject to X inactivation in females and is expressed from the active X chromosome only [8, 9]. The MCT8 gene contains 6 exons; the first exon in humans contains two possible translation initiation sites. Initiation from the first one yields a longer, 613-aa protein, while initiation from the second one results in a shorter, 539-aa protein. In some animals including rodents there is only a single initiation site corresponding to the shorter isoform . Although the identification of a ubiquitination target sequence in the N-terminus of the long isoform suggested faster proteasomal degradation, no differences in expression or function between the two isoforms have been revealed [2, 10-12]. The 58-66-kDa membrane-spanning protein possesses 12 putative TMDs  with intracellularly located N-and C-terminal domains. MCT8 contains an N-terminal PEST domain rich in proline, glutamic acid, aspartic acid, lysine, and arginine or histidine [8, 13]. This domain is usually associated with rapid protein turnover, but such has not been confirmed in the case of MCT8 [6, 14].
Almost all cells are targets of THs since these essential hormones regulate fat, protein, carbohydrate, and vitamin metabolism, affect protein synthesis, impact on the gastrointestinal tract and nerve differentiation, and the list is not exhaustive [15, 16]. T3 and its prohormone T4 enter the cells by active transport via transmembrane proteins [17, 18]. T3 can also be formed from T4 in the target cells, predominantly in the liver and brain. THs are produced via iodination of tyrosine in the follicular cells of the thyroid gland where they associate with thyroglobulin, a 660-kDa glycoprotein. Thyroid-stimulating hormone (TSH) of the anterior pituitary regulates the release of THs from the thyroid to the blood through the TSH receptors in the basolateral membrane of follicular cells. TSH also regulates the sodium/iodide symporter (NIS) that mediates the uptake of iodide. The amount of circulating THs regulate TSH release by a negative feedback mechanism. Based on their lipophilic structure THs were originally thought to enter the cells by passive diffusion; in recent years, however, multiple transporters have been shown to facilitate the uptake and efflux of THs by active transport. Besides MCT8, confirmed TH transporters include the other MCT family member MCT10, fatty acid translocase (FAT), LAT1, LAT2, OATP1A2, OATP1C1, OATP1B1, and OATP1B3 [9, 19, 20].
Mutations of MCT8 can lead to disturbed serum TH levels and TH-related disorders. Between 2004 and 2009, 60 years after AHDS was first documented, more than 40 types of mutation were identified in the SLC16A2 gene that cause partial or complete MCT8 inactivation [19, 21, 22]. The MCT8 S290F mutation was described in 4 generations of a family with AHDS. It was clarified that the substitution of Ser with Phe, rather than the loss of Ser per se, caused the dysfunction of MCT8 .
AHDS is a rare X-linked disease caused by defective T3 transport into neural cells during fetal development due to inherited recessive mutations of SLC16A2 . It is characterized by dysarthria, athetoid and dystonic movements, muscle hypoplasia, ataxia, central hypotonia, spasticity, and mental retardation [24, 25]. In the clinical findings, increased T3 is combined with normal or borderline-high TSH and low rT3 and T4 serum levels. This characteristic TH profile is the criteria for MCT8 mutation screening [19, 26]. Depending on the mutation, complete or partial inactivation of MCT8 may occur because of compromised TH transport capacity, defects in trafficking to the plasma membrane, or accelerated protein degradation [19, 23]. Humans have no alternative mechanism to compensate for MCT8 deficiency in the brain. Experiments of adeno-associated virus 9-based gene therapy were carried out on Mct8-deficient mice to increase the postnatal T3 uptake into the brain. Both short and long isoforms of human MCT8 were delivered intracerebroventricularly or intravenously. The results highlighted the importance of the isoform used and the delivery method and revealed that the therapeutic vector needs to be targeted to the BBB .
The transport of THs via MCT8 is inhibited by several compounds including the phenolphthalein dye bromsulphthalein (BSP) (IC50 ≈ 250 µM), the polymethine dye cardiogreen with an IC50 of 4 µM, and the soy isoflavone genistein with an IC50 of 31 µM. Silychristin, a main component of the silymarin complex of flavonolignans with antioxidant, antifibrotic and anti-inflammatory effects used in hepatic disorders, is a potent MCT8 inhibitor with an IC50 of 100 nM [27-29]. Abnormal serum TH levels and fatigue were observed in cancer patients treated with TKIs. In vitro experiments revealed that TKIs non-competitively inhibit TH uptake and efflux via MCT8 with IC50 values of 19, 22, 38, and 13 µM for dasatinib, sunitinib, imatinib, and bosutinib, respectively. These side-effect of TKIs, however, are not serious and usually well-tolerated [30, 31].
The current guidelines from FDA and EMA do not contain recommendations on in vitro testing of MCT8 inhibition for NCEs.
In vitro substrates used experimentally
brain, blood-brain barrier, liver, pituitary, placenta, heart, kidney, thyroid,
thyroid hormones (T4, T3, rT3, T2)
tyrosine kinase inhibitors, silychristin, genistein, BSP,
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