Function and regulation of OATP1B1 and OATP1B3

OATP1B1 和 OATP1B3 的功能和调节

• 批准号: 8666986
• 负责人: Wei Yue
• 金额: $ 19.95万
• 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/8666986
• 关键词: Function; regulation; OATP1B1; OATP1B3

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（由申请方提供）：肝摄取转运蛋白目前被认为是可变药物反应性和非预期药物相互作用的临床相关决定因素。有机阴离子转运多肽（OATP）1B 1和OATP 1B 3具有肝脏特异性，是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（包括降脂他汀类药物、抗生素、免疫抑制剂、强心苷、抗糖尿病药和抗癌药）从血液摄入肝脏的主要摄取转运蛋白。因此，OATP蛋白与人类健康具有重要的相关性。OATP 1B 1和OATP 1B 3的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OATP 1B 1和OATP 1B 3遗传多态性与许多底物的血浆浓度/全身暴露量显著增加相关（例如，他汀类药物、伊立替康、地高辛）。梭OATP 1B 1的512 T>C（V174 A）变异体是他汀类药物诱导的肌病的最稳健和最重要的预测因子。本研究项目的长期目标是确定通过OATP 1B 1和OATP 1B 3影响药物/毒素处置的分子机制，并预测和预防人体中OATP介导的药物相互作用。迄今为止，只有零星的信息是已知的有关机制参与调节OATP 1B 1和OATP 1B 3的功能，其中大部分是在转录水平上进行了研究。本申请的目的是阐明通过磷酸化和泛素系统进行的翻译后调节在调节OATP 1B 1和OATP 1B 3功能中的潜在作用。拟开展的研究基于以下初步结果：1）OATP 1B 3是一种磷酸化蛋白，OATP 1B 1和OATP 1B 3的功能受蛋白激酶C激活的调节; 2）泛素系统参与OATP 1B 1和OATP 1B 3的降解，蛋白酶体抑制影响OATP 1B 1和OATP 1B 3的功能。具体目标如下：目标1。阐明磷酸化状态改变对OATP 1B 1和OATP 1B 3转运功能和膜定位的影响。目标2.定义泛素系统对OATP 1B 1和OATP 1B 3降解和转运的调节。拟定的研究具有创新性，与人类健康相关，因为了解参与调节OATP 1B 1和OATP 1B 3功能的机制对于预测潜在的药物相互作用至关重要，并为药物开发提供有用的信息，以预防OATP介导的药物相互作用。这些实验的结果将大大拓宽我们预测和预防转运介导的药物相互作用的能力。