Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters.

Article Details

Citation

Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K

Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters.

Biochem Pharmacol. 2007 Jul 15;74(2):359-71. doi: 10.1016/j.bcp.2007.04.010. Epub 2007 Apr 13.

PubMed ID
17509534 [ View in PubMed
]
Abstract

The substrate specificities of human (h) multidrug and toxin extrusion (MATE) 1 and hMATE2-K were examined to find functional differences between these two transporters by the transfection of the cDNA of hMATE1 and hMATE2-K into HEK293 cells. Western blotting revealed specific signals for hMATE1 and hMATE2-K consistent with a size of 50 and 40kDa, respectively, in the transfectants as well as human renal brush-border membranes under reducing conditions. In the presence of oppositely directed H(+)-gradient, the transport activities of various compounds such as tetraethylammonium, 1-methyl-4-phenylpyridinium, cimetidine, metformin, creatinine, guanidine, procainamide, and topotecan were stimulated in hMATE1- and hMATE2-K-expressing cells. In addition to cationic compounds, anionic estrone sulfate, acyclovir, and ganciclovir were also recognized as substrates of these transporters. Kinetic analyses demonstrated the Michaelis-Menten constants for the hMATE1-mediated transport of tetraethylammonium, 1-methyl-4-phenylpyridinium, cimetidine, metformin, guanidine, procainamide, topotecan, estrone sulfate, acycrovir, and ganciclovir to be (in mM) 0.38, 0.10, 0.17, 0.78, 2.10, 1.23, 0.07, 0.47, 2.64, and 5.12, respectively. Those for hMATE2-K were 0.76, 0.11, 0.12, 1.98, 4.20, 1.58, 0.06, 0.85, 4.32, and 4.28, respectively. Although their affinity for hMATE1 and hMATE2-K was similar, the zwitterionic cephalexin and cephradine were revealed to be specific substrates of hMATE1, but not of hMATE2-K. Levofloxacin and ciprofloxacin were not transported, but were demonstrated to be potent inhibitors of these transporters. These results suggest that hMATE1 and hMATE2-K function together as a detoxication system, by mediating the tubular secretion of intracellular ionic compounds across the brush-border membranes of the kidney.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
CimetidineMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
CimetidineMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Substrate
Inhibitor
Details
CiprofloxacinMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
CiprofloxacinMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Inhibitor
Details
Estrone sulfateMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Details
Estrone sulfateMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Substrate
Details
GanciclovirMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Details
GanciclovirMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Substrate
Details
GuanidineMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Details
GuanidineMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Not AvailableDetails
LevofloxacinMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
LevofloxacinMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Inhibitor
Details
MetforminMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Substrate
Details
ProcainamideMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Details
ProcainamideMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Substrate
Details
TetraethylammoniumMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Details
TopotecanMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
TopotecanMultidrug and toxin extrusion protein 2ProteinHumans
Unknown
Substrate
Details
Polypeptides
NameUniProt ID
Multidrug and toxin extrusion protein 1Q96FL8Details
Multidrug and toxin extrusion protein 2Q86VL8Details