Molecular Characterization of Hepatic Organic Anion Transporting Polypeptides

肝脏有机阴离子转运多肽的分子表征

• 批准号: 7390611
• 负责人: BRUNO HAGENBUCH
• 金额: $ 27.78万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390611
• 关键词: 17p; Adverse effects; Affect; American; Antidiabetic Drugs; Bayer brand of cerivastatin sodium; Binding; Binding Sites; Biological Availability; Carrier Proteins; Cell Line; Charge; Chemicals; Chimera organism; Cholesterol; Combination Chemotherapy; Combination Drug Therapy; Data; Down-Regulation; Drug Interactions; Drug Transport; Drug effect disorder; Environment; Enzymes; Estradiol; Estrone-Sulfate; Fibrates; Fluo-3; Gemfibrozil; Genetic Polymorphism; Glucuronides; Goals; Hepatic; Hepatocyte; Hospitalization; Human; In Vitro; Knowledge; Laboratories; Lead; Ligands; Liver; Marketing; Mediating; Membrane; Membrane Transport Proteins; Miconazole; Modeling; Molecular; Nuclear Receptors; Numbers; OATP Transporters; Oocytes; Outcome; Patients; Pharmaceutical Preparations; Play; Proteins; Quantitative Structure-Activity Relationship; Research; Research Personnel; Risk; Role; Site; Site-Directed Mutagenesis; Structure; Substrate Specificity; System; Testing; Thiazolidinediones; Time; Transmembrane Domain; Triglycerides; Vaccinia virus; Withdrawal; Work; Xenobiotics; Xenopus laevis; base; cerivastatin; design; drug metabolism; experience; glucuronide; in vivo; inhibitor/antagonist; innovation; insight; novel therapeutics; prevent; programs; size; therapeutic target; three dimensional structure; uptake

DESCRIPTION (provided by applicant): Drug-drug interactions that occur at the level of drug transporters can have unexpected and severe side effects. The hepatic drug transporters of the organic anion transporting polypeptide (OATP) superfamily transport numerous endo- and xenobiotics (drugs) and are therefore important for drug disposition. The two liver specific OATP1B1 and OATP1B3 have broad and overlapping substrate specificity, but also transport distinct and unique substrates. However, there is nothing known about how OATPs recognize and transport different compounds. So far it is impossible to make exact predictions on whether a compound will be a substrate or not, and whether a possible drug-interaction might occur. Because OATPs are potential sites of drug-drug interactions that can lead to severe adverse effects, these unknowns should be clarified. Therefore, the long-term goal of the proposed studies is to understand, predict and prevent OATP related drug-drug interactions. The objective of this particular application is to determine the molecular basis of the polyspecificity of the liver-specific transporters, OATP1B1 and OATP1B3. The central hypothesis for the proposed research is that different substrates are transported by OATP1B1 and OATP1B3 using multiple transport/binding sites. Malfunction of these transporters (inhibition, up- or down-regulation, and polymorphisms) will affect drug bioavailability and can lead to adverse drug actions. We plan to test our central hypothesis and accomplish the overall objective of this application with the following four specific aims: 1) Characterize the substrate specificity of OATP1B1 and OATP1B3 with emphasis on nuclear receptor ligands; 2) Perform a detailed 3D-QSAR analysis for OATP1B1 and OATP1B3; 3) Determine the membrane topology; and 4) Identify the substrate binding sites of OATP1B1 and OATP1B3 using chimeras and site directed mutagenesis. A detailed understanding on how the liver specific drug transporters OATP1B1 and OATP1B3 recognize and transport their different substrates will help to predict and prevent adverse drug-drug interactions and to develop new therapeutic compounds to target the liver. Once this knowledge is available, there is the promise that it will be possible to develop safer medication which will result in less hospitalizations.

描述（由申请人提供）：在药物转运蛋白水平发生的药物相互作用可能会产生非预期的严重副作用。有机阴离子转运多肽（OATP）超家族的肝脏药物转运蛋白转运许多内源性和外源性药物（药物），因此对药物处置很重要。两种肝脏特异性OATP 1B 1和OATP 1B 3具有广泛和重叠的底物特异性，但也转运不同和独特的底物。然而，关于OATP如何识别和运输不同的化合物还没有任何了解。到目前为止，还不可能准确预测一种化合物是否会成为底物，以及是否可能发生药物相互作用。由于OATP是可能导致严重不良反应的药物相互作用的潜在位点，因此应澄清这些未知因素。因此，拟定研究的长期目标是了解、预测和预防OATP相关的药物相互作用。该特定应用的目的是确定肝脏特异性转运蛋白OATP 1B 1和OATP 1B 3的多特异性的分子基础。拟议研究的中心假设是OATP 1B 1和OATP 1B 3使用多个转运/结合位点转运不同底物。这些转运蛋白的功能障碍（抑制、上调或下调和多态性）将影响药物的生物利用度，并可能导致药物的不良反应。我们计划通过以下四个具体目标来检验我们的中心假设并实现本申请的总体目标：1）表征OATP 1B 1和OATP 1B 3的底物特异性，重点是核受体配体; 2）对OATP 1B 1和OATP 1B 3进行详细的3D-QSAR分析; 3）确定膜拓扑结构;和4）使用嵌合体和定点突变鉴定OATP 1B 1和OATP 1B 3的底物结合位点。详细了解肝脏特异性药物转运蛋白OATP 1B 1和OATP 1B 3如何识别和转运其不同的底物，将有助于预测和预防不良药物相互作用，并开发新的靶向肝脏的治疗化合物。一旦有了这些知识，就有可能开发出更安全的药物，从而减少住院率。