Functional characterization of human monocarboxylate transporter 6 (SLC16A5)

Murakami, Yoshiaki

doi:10.1124/dmd.105.005264

Cited by 53 publications

(90 citation statements)

References 28 publications

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“…7 Far less is known about the remaining family members up to now, although the number of studies to characterize the remaining orphan MCTs is increasing. For instance, for MCT6 transport of xenobiotics, such as loop diuretics (e.g., bumetanide), the antidiabetic drug nateglinide or the uricosuric agent probenecid was described 8, 9. In addition, in contrast to the typical MCT substrates, dietary flavonoids were recently proposed as substrate for MCT6, with additional inhibiting effect,10 suggesting distinct substrate specificities compared with MCT1–MCT4.…”

Section: Substrates Of Mct Transportersmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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Section: Substrates Of Mct Transportersmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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“…We have previously shown that MCT6 transports bumetanide, nateglinide, probenecid, and prostaglandin F 2a , but not L-lactic acid or L-tryptophan, which are typical substrates for MCT1-MCT4 and T-type amino acid transporter 1, respectively (Murakami et al, 2005). MCT6-mediated bumetanide uptake was pH-and membrane potential-dependent.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Monocarboxylate Transporter 6: Expression in Human Intestine and Transport of the Antidiabetic Drug Nateglinide

Kohyama¹,

Shiokawa²,

Ohbayashi³

et al. 2013

Drug Metab Dispos

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Monocarboxylate transporter (MCT) 6, encoded by SLC16A5, is a member of the monocarboxylate transporter family. Nateglinide, an oral hypoglycemic agent, quickly reaches the maximal serum concentration after its premeal administration. Although the functional existence of uptake systems for nateglinide in the intestine has been demonstrated, these transport systems have not yet been identified at the molecular level. The aim of this study was to demonstrate the localization of MCT6 in the human small intestine and characterize the transport properties of nateglinide via MCT6. Immunohistochemical analysis of the human small intestine revealed that anti-MCT6 antiserum stained the luminal side of the epithelial cells. When expressed in Xenopus laevis oocytes, MCT6-mediated uptake of [ 14 C]nateglinide was sensitive to extracellular pH and membrane potential. Furthermore, the K t value of nateglinide (45.9 mM) for MCT6 was lower than those previously reported in Caco-2 cells and rat intestinal brush-border membrane vesicles. In addition, probenecid, fluorescein, valproic acid, and salicylic acid, which are inhibitors of nateglinide uptake in Caco-2 cells and rat intestine, did not inhibit the uptake of nateglinide via MCT6. These results suggest that MCT6 may play a role in the intestinal absorption of nateglinide, although other transporters are also likely involved.

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“…Interestingly, the recent characterization of MCT6 showed that this isoform was involved in the transport of diuretics, such as bumetanide, and did not transport monocarboxylates (3).…”

Section: Influence Of Mcts On the Disposition Of Other Drugsmentioning

confidence: 99%

“…MCTs (SLC16A) were first identified in the mid-nineties and to date 14 members of this family have been identified through sequence homology (1,2). Currently, seven isoforms have been functionally characterized and it has been demonstrated that not all members function as proton-coupled transporters and that a wide variety of endogenous and exogenous compounds are substrates, including lactate, pyruvate, butyrate, γ-hydroxybutyrate, bumetanide, and simvastatin acid (3)(4)(5)(6). In contrast, the SMCT family contains only two members, SLC5A8 and SLC5A12, which were identified within the past 5 years (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

Morris

Felmlee

2008

AAPS J

184

146

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Abstract. The transport of monocarboxylates, such as lactate and pyruvate, is mediated by the SLC16A family of proton-linked membrane transport proteins known as monocarboxylate transporters (MCTs). Fourteen MCT-related genes have been identified in mammals and of these seven MCTs have been functionally characterized. Despite their sequence homology, only MCT1-4 have been demonstrated to be proton-dependent transporters of monocarboxylic acids. MCT6, MCT8 and MCT10 have been demonstrated to transport diuretics, thyroid hormones and aromatic amino acids, respectively. MCT1-4 vary in their regulation, tissue distribution and substrate/inhibitor specificity with MCT1 being the most extensively characterized isoform. Emerging evidence suggests that in addition to endogenous substrates, MCTs are involved in the transport of pharmaceutical agents, including γ-hydroxybuytrate (GHB), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), salicylic acid, and bumetanide. MCTs are expressed in a wide range of tissues including the liver, intestine, kidney and brain, and as such they have the potential to impact a number of processes contributing to the disposition of xenobiotic substrates. GHB has been extensively studied as a pharmaceutical substrate of MCTs; the renal clearance of GHB is dose-dependent with saturation of MCT-mediated reabsorption at high doses. Concomitant administration of GHB and L-lactate to rats results in an approximately two-fold increase in GHB renal clearance suggesting that inhibition of MCT1-mediated reabsorption of GHB may be an effective strategy for increasing renal and total GHB elimination in overdose situations. Further studies are required to more clearly define the role of MCTs on drug disposition and the potential for MCTmediated detoxification strategies in GHB overdose.

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Functional characterization of human monocarboxylate transporter 6 (SLC16A5)

Abstract: ABSTRACT:Human monocarboxylate transporter 6 (MCT6) has recently been isolated, and its tissue distribution has been established at the mRNA level, but its functional properties remain unknown.

Cited by 53 publications

References 28 publications

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Characterization of Monocarboxylate Transporter 6: Expression in Human Intestine and Transport of the Antidiabetic Drug Nateglinide

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

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