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: 10442070
• 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/10442070
• 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; 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; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pharmacy (field); Poison; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Publications; Publishing; Regulation; Research; Risk; Role; Source; System; Tenofovir; Testing; Time; Tissues; Toxin; Transmembrane Transport; Tubular formation; United States Environmental Protection Agency; Variant; apical membrane; base; basolateral membrane; disease registry; drug disposition; exposed human population; inhibitor; insight; kidney cell; mouse model; nephrotoxicity; 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.

项目概要/摘要 重金属镉（Cd）目前在美国有毒物质管理局2019年排名第7位 疾病登记处 (ATSDR) 并被美国环境保护署列为优先污染物之一 （美国环保局）。虽然现在很少见到因高浓度镉暴露而中毒的情况，但长期低浓度镉 暴露仍然是一个主要的健康问题，因为镉是一种累积金属，其生物半衰期极长 在人体内10-30年。镉暴露与多种疾病发病率增加有关。 引人注目的是，很少有人知道慢性镉暴露是否会影响用于治疗的药物的处置 疾病。肾转运蛋白通过介导跨肾小管细胞的药物转运来参与药物处置 特别是近端肾小管。通过摄取转运蛋白协调跨细胞转运，例如有机转运蛋白 基底外侧膜中的阳离子转运蛋白（OCT）和有机阴离子转运蛋白（OAT）与 外排转运蛋白，例如多药和毒素挤出蛋白（MATE）和多药耐药性相关 肾小管细胞顶膜中的蛋白质（MRP）被认为是肾功能的重要系统 分别处理阳离子和阴离子药物。我们最近的出版物和当前的初步结果 表明慢性镉暴露对肾脏转运蛋白（包括 OCT、MATE、OAT 和 MRP）有广泛影响。 然而，Cd 转运蛋白调节的详细机制及其对药物处置和药物处置的广泛影响 反应仍有待说明。我们假设慢性镉暴露可能会改变肾脏转运蛋白 功能，导致药物在肾脏中的分布和毒性的改变。为了检验这个假设，我们提出 开展具有三个具体目标的研究。首先，通过使用各种细胞和分子检测， 通过蛋白质组学方法，我们将揭示慢性镉暴露增强 OCT 和 OAT 摄取蛋白从细胞质池易位到细胞膜，从而 增加作为这些转运蛋白底物的小分子的细胞积累（目标 1）。最多 临床使用的药物要么是有机阳离子，要么是有机阴离子。然后我们建议展示的影响 通过研究镉暴露对 OCT 和 MATE 的影响，镉暴露对阳离子药物的处置 在小鼠肾组织和人肾细胞中的表达，特别是对顺铂处置的影响 和使用 Oct1/2- 和 Mate1-deficinet 小鼠的肾毒性（目标 2）。最后，慢性镉暴露的影响 将表征小鼠肾组织中阴离子药物转运蛋白 OAT 和 MRP 的表达 和人肾细胞，特别是镉对抗病毒药物替诺福韦的处置和肾毒性的影响 将使用 Oat1/3-、Mrp4 缺陷小鼠和 OAT 药理学抑制进行研究（目标 3）。成功的 该项目的完成将为发现环境中的镉作为以前未被认识到的 药物分布和反应的广泛变化的因素，有助于更好的药物治疗。