title: Ischemia/Reperfusion-inducible protein modulates the function of organic cation transporter 1 and multidrug and toxin extrusion 1.
abstract: The recently identified ischemia/reperfusion-inducible protein (IRIP) has been reported to negatively modulate the activities of several transporters in cell culture systems. 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. 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. In contrast, knockdown of IRIP by small hairpin RNA (shRNA) increased the transporter activities in vitro. IRIP overexpression decreased the membrane localization of transporter proteins without any changes in transcript levels in cells. 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). 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. In conclusion, IRIP negatively modulates the function of OCT1 and MATE1 in cells. Importantly, we provide in vivo evidence for such modulation that may cause an alteration in drug disposition. The regulation by IRIP on transporter activities likely occurs at a post-transcriptional level, and future studies are needed to characterize the exact mechanism.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, Maryland, United States.
authors: Qing
authors: Q
authors: Li
authors: Hyekyung
authors: H
authors: Yang
authors: Xiujuan
authors: X
authors: Peng
authors: Dong
authors: D
authors: Guo
authors: Zhongqi
authors: Z
authors: Dong
authors: James E
authors: JE
authors: Polli
authors: Yan
authors: Y
authors: Shu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000378:metabolism; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C503577:IRIP protein, mouse; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D016601:RNA-Binding Proteins; D008687:Metformin; D019204:GTP-Binding Proteins; C478762:YRDC protein, human
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