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)：肝脏摄取转运蛋白现在被认为是不同的药物反应和意外的药物相互作用的临床相关决定因素。有机阴离子转运多肽(OATP1B3)和有机阴离子转运多肽(OATP1B3)是肝脏特异性的主要摄取蛋白，介导多种内源性化合物(如胆汁酸)、环境毒素和许多临床重要药物的摄取，包括降脂他汀类药物、抗生素、免疫抑制剂、心苷类、降糖和抗癌药物。因此，OATP蛋白与人类健康具有重要的相关性。OATP1B1和OATP1B3功能障碍与药物药代动力学和毒性改变密切相关。转运功能降低的OATP1B1和OATP1B3基因多态性与血浆浓度显著升高/多种底物(如他汀类药物、伊立替康、地高辛)全身暴露有关。OATP1B1的c.512T&gt；C(V174A)变异是他汀类药物诱导的肌病最可靠和最重要的预测指标。该研究计划的长期目标是确定通过OATP1B1和OATP1B3影响药物/毒素处置的分子机制(S)，并预测和防止OATP介导的药物在人体内的相互作用。到目前为止，关于OATP1B1和OATP1B3功能的调控机制，人们只知道零星的信息，其中大部分是在转录水平上进行研究的。本应用的目的是阐明翻译后调节，通过磷酸化和泛素系统，在调节OATP1B1和OATP1B3功能中的潜在作用。这些研究基于我的初步研究结果：1)OATP1B3是一种磷酸化的蛋白质，OATP1B1和OATP1B3的功能受蛋白激酶C激活的调节；2)泛素系统参与了OATP1B1和OATP1B3的降解，蛋白酶体抑制影响了OATP1B1和OATP1B3的功能。具体目标如下：目的1.阐明磷酸化状态改变对OATP1B1和OATP1B3转运功能和膜定位的影响。目的2.明确泛素系统对OATP1B1和OATP1B3降解和转运的调控。这项研究具有创新性且与人类健康相关，因为了解OATP1B1和OATP1B3功能的调控机制(S)对于预测潜在的药物-药物相互作用至关重要，并为药物开发提供有用的信息，以防止OATP1B1和OATP1B3介导的药物-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-药物相互作用的能力。