STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT by
نویسنده
چکیده
The organic anion transporting polypeptides (human: OATP; other: Oatp) form a mammalian transporter superfamily that mediates the transport of structurally unrelated compounds across the cell membrane. Members in this superfamily participate in the absorption, distribution and excretion of many endogenous and exogenous substances including a number of medications and environmental toxicants. Polymorphisms of OATPs have been shown clinically to give rise to interindividual variabilities of drug efficacy and/or toxicity. Furthermore, as multi-specific transporters, they are potential sites for drug-drug interactions. Therefore, understanding the mechanism of OATP/Oatp mediated transport of endoand xenobiotics will not only help to improve drug efficacy but also to improve the prediction and prevention of toxicity. The overall goal of this dissertation is identifying key amino acids that may play an important role in OATP/Oatp-mediated transport and investigating the spatial size of the substrate binding/translocation pocket. In this dissertation, I defended three specific aims. In the first specific aim, I evaluated the hypothesis that conserved positively charged amino acids play important roles in OATP1B1 transport function. To address this aim, site-directed mutagenesis was employed and the mutants of several conserved positively charged amino acids were studied. The two extracellular amino acids R57 and K361 were found to be important in OATP1B1 mediated transport of estradiol-17β-glucuronide, estrone-3-sulfate and BSP. In the second specific aim, I evaluated the hypothesis that quantifying transport activities of different substrates mediated by chimeras between rat Oatp1a1 and
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