Impact of Cadmium Exposure on Transporter Function and Drug Disposition in the Kidney

镉暴露对肾脏转运功能和药物分布的影响

• 批准号: 10626140
• 负责人: Yan Shu
• 金额: $ 36.37万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-24 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626140
• 关键词: Affect; Anions; Antineoplastic Agents; Antiviral Agents; Biological; Biological Assay; Cadmium; Cardiovascular Diseases; Carrier Proteins; Cations; Cell membrane; Cell model; Cells; Chronic; Cisplatin; Clinical; Cytoplasmic Protein; Diabetes Mellitus; Disease; Dose Limiting; Drug Transport; Drug toxicity; Drug usage; Environment; Foundations; Half-Life; Health; Heavy Metals; Human; Human body; Incidence; Individual; Intoxication; Kidney; Knowledge; Malignant Neoplasms; Mediating; Membrane; Metals; Molecular; Multidrug Resistance-Associated Proteins; Mus; Organic Anion Transporters; Organic Cation Transporter; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Pharmacy (field); Poison; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Publications; Publishing; Regulation; Research; Risk; Role; Source; System; Tenofovir; Testing; Tissues; Toxin; Transmembrane Transport; Tubular formation; United States Environmental Protection Agency; Variant; Viral; apical membrane; basolateral membrane; disease registry; drug disposition; exposed human population; inhibitor; insight; kidney cell; mouse model; nephrotoxicity; pharmacologic; pollutant; protein transport; response; side effect; small molecule; toxic metal; toxicant; trafficking; uptake

PROJECT SUMMARY/ABSTRACT The heavy metal cadmium (Cd) is currently ranked 7th on the 2019 US Agency for Toxic Substances and Disease Registry (ATSDR) and listed as one of Priority Pollutants by US Environmental Protection Agency (EPA). Although intoxication by high levels of Cd exposure is rarely seen nowadays, chronic low levels of Cd exposure is still a major health concern as Cd is a cumulative metal with an extremely long biological half-life of 10-30 years in human body. Cd exposure has been associated with increased incidence of multiple diseases. Strikingly, little is known whether chronic Cd exposure would affect the disposition of drugs that are used to treat diseases. Renal transporter proteins involve in drug disposition by mediating drug transport across tubular cells and particularly proximal tubules. Coordinated transcellular transport by uptake transporters, such as organic cation transporters (OCTs) and organic anion transporters (OATs) in the basolateral membrane in concert with efflux transporters, such as multidrug and toxin extrusion proteins (MATEs) and multidrug resistance-associated proteins (MRPs) in the apical membrane of tubular cells, is believed to be an essential system for renal disposition of cationic and anionic drugs, respectively. Our recent publications and current preliminary results indicate a broad effect by chronic Cd exposure on renal transporters including OCTs, MATEs, OATs and MRPs. However, the detail mechanism of transporter regulation by Cd and its broad impact on drug disposition and response remain to be illustrated. We hypothesize that chronic Cd exposure could alter renal transporter function, resulting in alteration in drug disposition and toxicity in the kidney. To test this hypothesis, we propose to conduct research with three specific Aims. Firstly, by using a variety of cellular and molecular assays, along with proteomic approach, we will uncover a molecular mechanism by which chronic Cd exposure enhances the translocation of OCT and OAT uptake proteins from the cytoplasmic pool to cell membrane and consequently increase the cellular accumulation of small molecules that are the substrates of these transporters (Aim 1). Most clinical used drugs are either organic cations or organic anions. We then propose to demonstrate the impact of Cd exposure on the disposition of cationic drugs by investigating the effects of Cd exposure on OCT and MATE expression in mouse kidney tissues and human renal cells, and particularly the impact on cisplatin disposition and nephrotoxicity using Oct1/2- and Mate1-deficinet mice (Aim 2). Lastly, the effects of chronic Cd exposure on expression of the anionic drug transporters OATs and MRPs will be characterized in mouse kidney tissues and human renal cells, and specifically Cd impact on the disposition and nephrotoxicity of the antiviral tenofovir will be studied with Oat1/3-, Mrp4-deficient mice and OAT pharmacological inhibition (Aim 3). Successful completion of this project will provide a foundation to uncover environmental Cd as a previously unrecognized factor for the broad variation in drug disposition and response, contributing to a better drug theray.

项目摘要/摘要 重金属镉（CD）目前在2019年美国有毒物质和 疾病登记处（ATSDR），并被美国环境保护局列为优先污染物之一 （EPA）。尽管如今很少见到高水平的CD暴露，但慢性低CD 暴露仍然是一个主要的健康问题，因为CD是一种累积金属，其生物半衰期非常长 人体10 - 30年。 CD暴露与多种疾病的发生率增加有关。 令人惊讶的是，鲜为人知的慢性CD暴露是否会影响用于治疗的药物的处置 疾病。肾脏转运蛋白涉及药物处置，通过介导跨管状细胞的药物转运 特别是近端小管。通过摄取转运蛋白（例如有机）协调的跨细胞运输 阳离子转运蛋白（OCT）和基底外侧膜中的有机阴离子转运蛋白（燕麦）与 外排转运蛋白，例如多药和毒素挤出蛋白（伴侣）以及与多药抗性相关的 据信，蛋白质（MRP）被认为是肾脏的必不可少的系统 阳离子和阴离子药物的处置。我们最近的出版物和当前的初步结果 表明慢性CD暴露对包括OCT，伴侣，燕麦和MRP在内的肾脏转运蛋白产生了广泛的影响。 但是，通过CD调节转运蛋白调节的细节机制及其对药物处置的广泛影响和 响应仍有待说明。我们假设慢性CD暴露会改变肾脏转运蛋白 功能，导致肾脏的药物处置和毒性改变。为了检验这一假设，我们提出了 以三个特定目标进行研究。首先，通过使用各种细胞和分子测定 使用蛋白质组学方法，我们将发现一种分子机制，慢性CD暴露增强 OCT和燕麦摄取蛋白从细胞质池转移到细胞膜，因此易位 增加小分子的细胞积累，这些分子是这些转运蛋白的底物（AIM 1）。最多 临床使用的药物是有机阳离子或有机阴离子。然后，我们建议证明 通过研究CD暴露对OCT和伴侣的影响，CD暴露于阳离子药物的处置 小鼠肾脏组织和人肾细胞的表达，尤其是对顺铂的影响 使用OCT1/2-和MATE1-胜过小鼠的肾毒性（AIM 2）。最后，慢性CD暴露的影响 在小鼠肾脏组织中，将在阴离子药物转运蛋白和MRP的表达上表征 和人类肾细胞，特别是CD对抗病毒替诺福韦的处置和肾毒性的影响 将使用OAT1/3-，MRP4缺陷型小鼠和OAT药理抑制（AIM 3）研究。成功的 该项目的完成将为揭示环境CD的基础，作为先前未知的 药物处置和反应的广泛差异因素，导致更好的药物。