![]() Notably, OCTs and MATEs share a broad spectrum of substrates and inhibitors 24. The MATEs such as human MATE1 and MATE2K are located in the apical membrane of hepatocytes and/or renal proximal tubular cells. More recently, the multidrug and toxin extrusion (MATE, SLC47A) proteins have been identified and characterized as H +/organic cation antiporters mediating the excretion of cationic compounds into bile and urine 20– 23. ![]() Nevertheless, it remains to determine whether IRIP has other targets and the regulation exists in vivo having an effect on drug disposition.ĭisposition of certain cationic compounds is determined by cellular uptake via OCTs which are expressed in the basolateral membrane of hepatocytes and renal proximal tubular cells 3, 18, 19. The only function reported for the higher eukaryotic IRIP homologues is the regulation of transporter activities 8, 9. However, the underlying mechanisms of these functions are still unknown. Attempts have been made to understand their functions in tRNA modification 11, ribosome biogenesis 12, 13 and normal growth 14– 17 in prokaryotes and yeast. Found in all sequenced genomes to date, the Sua5-YicO-YrdC family has been ranked in the top ten conserved hypothetical proteins to be considered as high priority for experimental study 10. IRIP represents the mammalian member of a protein family containing Sua5-YicO-YrdC domain 8. The recently identified ischemia/reperfusion-inducible protein (IRIP) regulates a variety of both uptake and efflux transporters including dopamine transporter (DAT), norepinephrine transporter (NET), serotonin transporter (SERT), OCT2, OCT3, organic anion transporter 1 (OAT1), and P-glycoprotein (P-gp) in cell culture systems 8, 9. Despite their clinical significance, many xenobiotic transporters, particularly those uptake transporters including OCT1, are poorly characterized in their regulation. Among recognized examples, the organic cation transporter 1 (OCT1 SLC22A1) has been demonstrated by us as a key determinant of the therapeutic response to metformin 6, 7, one of top prescription drugs in the United States. The critical role of xenobiotic transporter proteins in the disposition of clinically used drugs has been well appreciated 1– 5. The regulation by IRIP on transporter activities likely occurs at a post-transcriptional level, and future studies are needed to characterize the exact mechanism. Importantly, we provide in vivo evidence for such modulation that may cause an alteration in drug disposition. In conclusion, IRIP negatively modulates the function of OCT1 and MATE1 in cells. In addition, we observed that the expression of IRIP was approximately half ( P < 0.01) in ob/ob mice when compared to their lean littermates, with significant increases in hepatic Oct1 protein expression and metformin accumulation. By overexpressing IRIP in mouse liver via hydrodynamic tail vein injection, we demonstrated that increased IRIP expression could cause a significant reduction in hepatic accumulation of metformin ( P < 0.01). ![]() IRIP overexpression decreased the membrane localization of transporter proteins without any changes in transcript levels in cells. In contrast, knockdown of IRIP by small hairpin RNA (shRNA) increased the transporter activities in vitro. In the uptake studies in the human embryonic kidney 293 cells overexpressing IRIP with and without OCT1 or MATE1, IRIP overexpression was found to significantly inhibit the uptake of 1-methyl-4-phenylpyridinium mediated by OCT1 or MATE1. The goal of this study is to determine whether IRIP regulates the activities of OCT1 and MATE1, and hence the disposition in vivo of their substrate metformin, a therapeutic drug for diabetes and other obesity-related syndromes. The recently identified ischemia/reperfusion-inducible protein (IRIP) has been reported to negatively modulate the activities of several transporters in cell culture systems.
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