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. ![]() iRip transfers music from your iPod back to your iTunes Library, allows you to listen to music directly on your iPod (thus saving valuable disk space) and it supports major formats. The recently identified ischemia/reperfusion-inducible protein (IRIP) has been reported to negatively modulate the activities of several transporters in cell culture systems. Fortunately, applications such as iRip (formerly known as iPodRip) make this problem a thing of the past by unlocking your iPod so that you can use it as you want.
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