Substrate-dependent inhibition of human MATE1 by cationic ionic liquids.

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Martinez-Guerrero LJ, Wright SH

Substrate-dependent inhibition of human MATE1 by cationic ionic liquids.

J Pharmacol Exp Ther. 2013 Sep;346(3):495-503. doi: 10.1124/jpet.113.204206. Epub 2013 Jun 19.

PubMed ID

23785176 [ View in PubMed

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Abstract

The multidrug and toxin extruders 1- and 2-K (MATE1 and MATE2-K) are expressed in the luminal membrane of renal proximal tubule cells and provide the active step in the secretion of molecules that carry a net positive charge at physiologic pH, so-called organic cations. The present study tested whether structurally distinct MATE substrates can display different quantitative profiles of inhibition when interacting with structurally distinct ligands. The tested ligands were three structurally similar cationic ionic liquids (ILs, salts in the liquid state: N-butylpyridinium, NBuPy; 1-methyl-3-butylimidazolium, Bmim; and N-butyl-N-methylpyrrolidinium, BmPy). Uptake was measured using Chinese hamster ovary cells that stably expressed MATE1 or MATE2-K. By trans-stimulation, all three ILs were transported by both MATE transporters. The three ILs also inhibited uptake of three structurally distinct MATE substrates: 1-methyl-4-phenylpyridinium (MPP), triethylmethylammonium (TEMA), and N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA). MATE1 displayed a higher affinity for the pyridinium-based NBuPy (IC50 values, 2-4 microM) than for either the pyrrolidinium- (BmPy; 20-70 microM) or imidazolium-based ILs (Bmim; 15-60 microM). Inhibition of MPP, TEMA, and NBD-MTMA transport by NBuPy was competitive, with comparable Ki values against all substrates. Bmim also competitively blocked the three substrates but with Ki values that differed significantly (20 microM against MPP and 30 microM against NBD-MTMA versus 60 microM against TEMA). Together, these data indicate that renal secretion of ILs by the human kidney involves MATE transporters and suggest that the mechanism of transport inhibition is ligand-dependent, supporting the hypothesis that the binding of substrates to MATE transporters involves interaction with a binding surface with multiple binding sites.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Metformin	Multidrug and toxin extrusion protein 1	Protein	Humans	Unknown	Substrate	Details