Multidrug and toxin extrusion family SLC47: Physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K

doi:10.1016/j.mam.2012.11.004

Molecular Aspects of Medicine

Volume 34, Issues 2–3, April–June 2013, Pages 661-668

https://doi.org/10.1016/j.mam.2012.11.004 Get rights and content

Abstract

The kidney plays an important role in the secretion of organic compounds including drugs, toxins and endogeneous metabolites. The renal elimination process of organic cations is mediated by two distinct transport systems expressed on the apical and basolateral membrane of proximal epithelial cells. In 2005, mammalian multidrug and toxin extrusion 1 (MATE1)/SLC47A1 was identified as an orthologue of bacterial NorM. MATE1 is the H⁺/organic cation antiporter at the apical membrane, which mediates the secretion of organic cations. Kidney-specific MATE2-K was isolated from human kidney and localized at the brush-border membrane of proximal tubules. Like MATE1, MATE2-K mediates the secretion of organic cations into urine. MATE1 and MATE2-K are involved in the excretion of important medications and the disruption of these transporters can cause severe pharmacological problems. Recent findings regarding the MATE/SLC47 family are summarized in this review.

Introduction

The renal organic cation transport system plays an important role in the excretion of drugs, toxins and endogenous metabolites into urine. The secretion process across the tubular epithelial cells in the kidney is mediated by two distinct systems on the apical and the basolateral membranes (Inui et al., 2000). In the 1980s, the functions of membrane transporters were characterized using isolated membrane vesicles from renal proximal tubules. It was indicated that the electrogenic transport of organic cations at the basolateral membrane was facilitated by a difference in membrane potential. Conversely, transport at the brush-border membrane is driven by an opposite H⁺ gradient (Takano et al., 1984).

Organic cation transporter (OCT) 1 was first isolated from the kidney in 1994 (Grundemann et al., 1994). OCT2 was identified two years later (Okuda et al., 1996). Transport activities of OCT1 and OCT2, encoded by the SLC22A1 and SLC22A2 genes, are facilitated by the membrane potential difference. Although the expression level of OCT1 in human kidney cortex was quite low, OCT2 was highly expressed at the basolateral membrane of renal proximal tubules (Motohashi et al., 2002). Thus, OCT2 is the predominant organic cation transporter at the basolateral membrane of epithelial cells in human kidney. Physiological and pharmacological roles of OCTs have been investigated from various viewpoints. Several excellent reviews describe the progress in the research of OCT family (Burckhardt and Wolff, 2000, Inui et al., 2000, Jonker and Schinkel, 2004, Koepsell et al., 2007, Wright, 2005).

In 2005, mammalian multidrug and toxin extrusion (MATE) was identified as an orthologue of the bacterial MATE family (Otsuka et al., 2005). Human MATE1, encoded by the SLC47A1 gene, is primarily expressed in the kidney and liver, where it is localized to the luminal membranes of the renal tubules and bile canaliculi. MATE1 mediates the H⁺-coupled electroneutral exchange of tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP). These compounds are typical substrates of renal and hepatic H⁺-coupled organic cation antiporters.

Several noteworthy review articles have been published about MATE1 and MATE2-K (Omote et al., 2006, Terada and Inui, 2008, Yonezawa and Inui, 2011a, Yonezawa and Inui, 2011b). This review summarizes recent topics relating to the MATE (SLC47) family.

Section snippets

Cloning of MATE

The mammalian SLC47 family have been identified as homologs of the NorM Na⁺/multidrug antiporter in Vibrio parahaemolyticus. The SLC47A1 and SLC47A2 genes encoding MATE1 and MATE2 were first identified in 2005 (Otsuka et al., 2005). Human and rodent MATE1 are primarily expressed in the kidney and liver (Fig. 1), where they are localized to the luminal membranes of the renal tubules and the bile canaliculi (Hiasa et al., 2006, Ohta et al., 2006, Terada et al., 2006). MATE1 mediates H⁺-coupled

Substrate specificity

Although MATEs recognize substrates similar to the OCT family, MATEs can transport zwitterions and anionic compounds in addition to cationic drugs. MATE1 and MATE2-K were found to have functional differences between two transporters (Tanihara et al., 2007). In addition to cationic compounds such as TEA, MPP, cimetidine, metformin, guanidine, procainamide and topotecan, anionic estrone sulfate, acyclovir, and ganciclovir were also recognized as substrates of these transporters. Although their

Drug–drug interaction involving the MATE family

Apical efflux by the MATE family is considered one of the sites of drug–drug interaction in addition to OCT at basolateral membrane (Ito et al., 2012, Matsushima et al., 2009, Tsuda et al., 2009b). Epithelial cells engineered to express both human OCT2 and MATE transporters are required to simultaneously evaluate drug interactions with renal basolateral and apical organic cation transporters. Tsuda et al. (2009b) assessed the interaction between cimetidine and metformin with double-transfected

Conclusion

In this mini review, we summarized recent findings regarding the molecular structure, transport function, physiological roles and clinical importance of MATE/SLC47. MATE1 and MATE2-K play major roles in the renal secretion of organic cations at the brush-border membranes, co-operating with basolateral OCT2 at tubular epithelial cells in human kidney. As well as OCT2, MATE1 and MATE2-K may be the sites of interaction between cationic drugs. In addition, recent reports suggested that disruption

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgements

This work was supported in part by a Grant-in aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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^☆: Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch”.

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ReviewMultidrug and toxin extrusion family SLC47: Physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K☆

Abstract

Introduction

Section snippets

Cloning of MATE

Substrate specificity

Drug–drug interaction involving the MATE family

Conclusion

Conflict of interest

Acknowledgements

Kidney Int.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Trends Pharmacol. Sci.

Biochem. Pharmacol.

Biochim. Biophys. Acta

Biochem. Pharmacol.

Biochem. Pharmacol.

Toxicol. Appl. Pharmacol.

Biochem. Pharmacol.

Identification of essential histidine and cysteine residues of the H+/organic cation antiporter multidrug and toxin extrusion (MATE)

Mol. Pharmacol.

Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study

Diabetes

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response

Pharmacogenet. Genomics

Structure of renal organic anion and cation transporters

Am. J. Physiol. Renal. Physiol.

Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family

J. Pharmacol. Exp. Ther.

A common 5’-UTR variant in MATE2-K is associated with poor response to metformin

Clin. Pharmacol. Ther.

Interaction of H+ with the extracellular and intracellular aspects of hMATE1

Am. J. Physiol. Renal. Physiol.

Drug excretion mediated by a new prototype of polyspecific transporter

Nature

Structure of a cation-bound multidrug and toxic compound extrusion transporter

Nature

Wide variety of locations for rodent MATE1, a transporter protein that mediates the final excretion step for toxic organic cations

Am. J. Physiol. Cell Physiol.

Functional characterization of testis-specific rodent multidrug and toxic compound extrusion 2, a class III MATE-type polyspecific H+/organic cation exporter

Am. J. Physiol. Cell Physiol.

Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug–drug interactions caused by cimetidine in the kidney

J. Pharmacol. Exp. Ther.

Review
Multidrug and toxin extrusion family SLC47: Physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K☆

Identification of essential histidine and cysteine residues of the H⁺/organic cation antiporter multidrug and toxin extrusion (MATE)

Interaction of H⁺ with the extracellular and intracellular aspects of hMATE1

Functional characterization of testis-specific rodent multidrug and toxic compound extrusion 2, a class III MATE-type polyspecific H⁺/organic cation exporter