Substrate-Dependent Inhibition of Human MATE1 by Cationic Ionic Liquids

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