Function and regulation of OATP1B1 and OATP1B3

OATP1B1 和 OATP1B3 的功能和调节

• 批准号: 8532684
• 负责人: Wei Yue
• 金额: $ 26.86万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532684
• 关键词: Adenovirus Vector; Adverse effects; Affect; Aging; Antibiotics; Antidiabetic Drugs; Antineoplastic Agents; Bile Acids; Blood; Cardiac Glycosides; Carrier Proteins; Cell Line; Computer Simulation; Data; Digoxin; Disease; Drug Interactions; Drug Kinetics; Drug Transport; Functional disorder; Gene Expression; Genetic Polymorphism; Goals; Green Fluorescent Proteins; Health; Hepatic; Hepatocyte; Human; Immunosuppressive Agents; Lipids; Literature; Liver; Mediating; Membrane; Modeling; Molecular; Mutagenesis; Myopathy; OATP Transporters; Outcome; Pharmaceutical Preparations; Phosphorylation; Plasma; Post-Translational Regulation; Proteasome Inhibition; Proteasome Inhibitor; Protein Kinase C; Proteins; Regulation; Research; Role; Serine; Substrate Interaction; System; Testing; Toxic Environmental Substances; Toxic effect; Toxin; Ubiquitin; Variant; Work; base; clinically relevant; drug candidate; drug development; innovation; irinotecan; kinase inhibitor; liver-specific protein; novel; novel strategies; overexpression; prevent; programs; protein function; research study; success; trafficking; uptake

DESCRIPTION (provided by applicant): Hepatic uptake transport proteins are now recognized as clinically relevant determinants of variable drug responsiveness and unexpected drug-drug interactions. Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are liver-specific, and are major uptake transport proteins that mediate uptake, from blood into the liver, of a diverse array of endogenous compounds (e.g. bile acids), environmental toxins, and many clinically important drugs, including lipid-lowering statins, antibiotics, immunosuppressants, cardiac glycosides, antidiabetic and anticancer agents. Therefore, OATP proteins have significant relevance to human health. Dysfunction of OATP1B1 and OATP1B3 is closely related with altered drug pharmacokinetics and toxicity. Genetic polymorphisms of OATP1B1 and OATP1B3 that have decreased transport function are associated with markedly increased plasma concentrations/systemic exposure of many substrates (e.g., statins, irinotecan, digoxin). The c. 512T>C (V174A) variant of OATP1B1 is the most robust and important predictor of statin-induced myopathy. The long-term goal of this research program is to define the molecular mechanism(s) that affect drug/toxin disposition through OATP1B1 and OATP1B3, and to predict and prevent OATP-mediated drug-drug interactions in humans. To date, only scattered information is known regarding mechanisms involved in regulating OATP1B1 and OATP1B3 function, most of which were studied at the transcriptional level. The objectives of this application are to elucidate the potential role of posttranslational regulation, via phosphorylation and the ubiquitin system, in modulating OATP1B1 and OATP1B3 function. The proposed studies are based on my preliminary results that: 1) OATP1B3 is a phosphorylated protein and the function of OATP1B1 and OATP1B3 is regulated by protein kinase C activation; 2) the ubiquitin system is involved in OATP1B1 and OATP1B3 degradation, and proteasome inhibition affects OATP1B1 and OATP1B3 function. The specific aims are as follows: Aim 1. Elucidate the impact of altered phosphorylation status on OATP1B1 and OATP1B3 transport function and membrane localization. Aim 2. Define the regulation of OATP1B1 and OATP1B3 degradation and trafficking by the ubiquitin system. The proposed research is innovative and relevant to human health because an understanding of the mechanism(s) that are involved in regulating OATP1B1 and OATP1B3 function is essential to predict potential drug-drug interactions, and provide helpful information in drug development to prevent OATP-mediated drug- drug interactions. The outcomes of these experiments will greatly broaden our ability to predict and prevent transport-mediated drug-drug interactions.

描述（由申请人提供）：肝摄取转运蛋白现在被认为是可变药物反应性和意外药物相互作用的临床相关决定因素。 Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are liver-specific, and are major uptake transport proteins that mediate uptake, from blood into the liver, of a diverse array of endogenous compounds (e.g. bile acids), environmental toxins, and many clinically important drugs, including lipid-lowering statins, antibiotics, immunosuppressants, cardiac糖苷，抗糖尿病和抗癌剂。因此，OATP蛋白与人类健康具有重要意义。 OATP1B1和OATP1B3的功能障碍与药物药代动力学和毒性的改变密切相关。运输功能降低的OATP1B1和OATP1B3的遗传多态性与许多底物的血浆浓度/系统暴露显着增加有关（例如汀类药物，伊立替康，地高辛）。 c。 OATP1B1的512T> C（V174A）变体是他汀类药物诱导的肌病的最强大，最重要的预测指标。该研究计划的长期目标是定义通过OATP1B1和OATP1B3影响药物/毒素处置的分子机制，并预测和预测和预防OATP介导的人类中的药物相互作用。迄今为止，仅知道有关调节OATP1B1和OATP1B3功能的机制的散射信息，其中大多数是在转录级别进行了研究的。本应用的目标是通过磷酸化和泛素系统阐明翻译后调节的潜在作用，在调节OATP1B1和OATP1B3功能中。提出的研究是基于我的初步结果，即：1）OATP1B3是一种磷酸化蛋白，OATP1B1和OATP1B3的功能受蛋白激酶C的激活调节。 2）泛素系统参与OATP1B1和OATP1B3降解，蛋白酶体抑制会影响OATP1B1和OATP1B3功能。具体目的如下：目标1。阐明改变磷酸化状态对OATP1B1和OATP1B3传输功能和膜定位的影响。 AIM 2。定义OATP1B1和OATP1B3降解和贩运系统的调节。拟议的研究具有创新性，并且与人类健康有关，因为对调节OATP1B1和OATP1B3功能的机制的理解对于预测潜在的药物毒品相互作用至关重要，并为药物开发提供了有用的信息，以防止OATP介导的药物相互作用。这些实验的结果将极大地扩大我们预测和防止运输介导的药物相互作用的能力。