Interactions between metabolism, transport, and toxicity of benzalkonium chlorides

苯扎氯铵的代谢、运输和毒性之间的相互作用

• 批准号: 10207171
• 负责人: Libin Xu
• 金额: $ 46.36万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10207171
• 关键词: 3-Dimensional; ABCB1 gene; Active Biological Transport; Address; Affect; Benzalkonium Chloride; Bile Acids; Biological; Biological Markers; Blood; COVID-19 pandemic; CYP2D6 gene; Carboxylic Acids; Carrier Proteins; Case Study; Cell Death; Cell Line; Cells; Cholesterol; Chronic; Complement; Cytochrome P450; Data; Dermal; Development; Disinfectants; Environmental Pollution; Epithelial Cells; Exposure to; Food processing industry; Gene Expression; Genetic Variation; Glucuronides; Goals; Healthcare; Hepatocyte; Homeostasis; Human; Hydroxylation; In Vitro; Ingestion; Inhalation; Injury to Kidney; Intake; Kidney; Knowledge; Lipids; Liver; Local Anti-Infective Agents; Medical; Metabolic; Metabolism; Mus; Neurologic; Oral; Oral Ingestion; Organ; Organic Cation Transporter; Outcome; Participant; Pathway interactions; Phase; Plasma; Population; Prevention; Protein Isoforms; Proteins; Proximal Kidney Tubules; Rattus; Reporting; Research; Rodent; Route; Safety; Sampling; Side; Sterols; System; Testing; Time; Tissues; Toxic effect; Toxicology; Toxin; United States National Institutes of Health; Urine; Work; Xenobiotics; antimicrobial; cell injury; consumer product; cytotoxicity; experimental study; gene environment interaction; high risk; human disease; inhibitor/antagonist; innovation; kidney cell; lipid metabolism; lipidomics; man; microphysiology system; nephrotoxicity; novel; organ on a chip; oxidation; reproductive; respiratory; transcriptome sequencing; transcriptomics; uptake

Project Summary Benzalkonium chlorides (BACs) are widely used antimicrobials in disinfecting products, medical products, consumer products, and food processing industries, suggesting humans may be exposed chronically and sys- temically to BACs through a variety of routes. Our preliminary study found that close to 50 of 100 random hu- man plasma samples contain detectable levels of BACs, suggesting BACs are indeed absorbed. The ongoing COVID-19 pandemic has led to greatly increased use of BAC-containing disinfectants, which is concerning given accumulating evidence in respiratory, developmental, reproductive, and neurological toxicities inflicted by BACs and BAC-induced disruption of cholesterol and lipid homeostasis in rodents. However, there is a lack of knowledge on the metabolism, transport, and biological consequences of BACs in humans. Our goal is to characterize the pathways of metabolism and transport of BACs and their impact on nephrotoxicity of BACs. The potential for nephrotoxicity is supported by previous studies in rats showing that BACs accumulate to the highest level in the kidney after oral intake and our preliminary studies showing that BACs exert potent cytotox- icity in a 3D “kidney-on-a-chip” microphysiological system (MPS). Recently, we reported that BACs are metab- olized by human cytochrome P450 (CYP) isoforms CYP2D6 and CYP4s in vitro. Furthermore, we found that BACs are actively transported by human organic cation transporters (hOCTs). Because CYP2D6, CYP4s, and hOCTs are highly polymorphic with greatly varying protein activities, we hypothesize that toxicities of BACs in kidney are dependent on the activities of BAC-metabolizing and transporting proteins in both liver and kidney. In Aim 1, we will characterize pathways of metabolism and transport of BACs in vitro, including secondary me- tabolism by β-oxidation and glucuronidation and transport by hOCTs, human multidrug and toxin extrusion pro- teins, and P-glycoprotein. In Aim 2, we will evaluate nephrotoxicity induced by BACs in human proximal tubule epithelial cells in 3D integrated liver-kidney “organs-on-chips” MPS. An integrated sterolomics, lipidomics, and transcriptomics approach will be used to systemically assess the toxicity and biological activities of BACs. In Aim 3, we will assess BAC exposure levels and their correlation with lipid and kidney injury biomarkers in hu- mans, as well as the impact of genetic variations on BAC metabolism and disposition. The significance of this project lies in that it will, for the first time, address the knowledge gap in metabolism, transport, and toxicity of BACs in humans. Elucidation of the contribution of reduced activities in CYPs and/or transporters to BAC tox- icity would enable us to identify high-risk human population with genetic variations in these proteins. The gained knowledge could also inform federal agencies on setting more appropriate exposure limitations. The innovation of this project lies in a) a novel example of gene-environment interaction through xenobiotic- processing proteins, b) the use of an integrated liver-kidney MPS to assess the toxicological consequences of xenobiotics, and c) integrated omics for rigorous systems toxicology studies.

项目摘要 苯扎氯铵(BAC)是广泛用于消毒产品、医疗产品、 消费品和食品加工业，这表明人类可能长期接触和SYS- 临时地通过各种路线到达BAC。我们的初步研究发现，在100个随机的人中，有近50人 人体血浆样本中含有可检测到的BAC水平，这表明BAC确实被吸收了。正在进行的 新冠肺炎疫情导致含有生物制品的消毒剂使用量大幅增加，这令人担忧 给出了在呼吸、发育、生殖和神经毒性方面积累的证据 BACS和BAC诱导的啮齿动物胆固醇和脂类稳态的破坏。然而，目前还缺乏 关于细菌在人体内的代谢、转运和生物学后果的知识。我们的目标是 描述BAC的代谢和转运途径及其对BAC肾毒性的影响。 先前在大鼠身上进行的研究表明，BAC累积到 口服后肾脏中的最高水平和我们的初步研究表明，BAC发挥强大的细胞毒素- ICity是一种3D“芯片肾脏”微生理系统(MPS)。最近，我们报道了BAC是Metab- 在体外被人细胞色素P450(CYP)亚型所溶解的细胞色素P450(CYP)亚型是细胞色素P450的亚型。此外，我们发现， BACs由人的有机阳离子转运体(HOCTs)主动转运。因为CYP2D6、CYP4和 HOCT是高度多态的，蛋白质活性变化很大，我们假设BAC在 肾脏依赖于BAC在肝脏和肾脏中代谢和运输蛋白质的活动。 在目标1中，我们将描述BAC在体外的代谢和转运途径，包括继发代谢和转运途径。 β氧化代谢和葡萄糖糖醛酸化代谢及hOCTs转运，人多药和毒素排泄蛋白 和P-糖蛋白。在目标2中，我们将评估BAC对人近端小管的肾毒性。 3D一体化肝肾“芯片器官”MPS中的上皮细胞。综合的类固醇组学、脂类组学和 将使用转录组学方法系统地评估BAC的毒性和生物活性。在……里面 目的3，我们将评估BAC暴露水平及其与血脂和肾脏损伤生物标志物的相关性。 以及遗传变异对BAC新陈代谢和性情的影响。这件事的意义 该项目的关键在于，它将首次解决新陈代谢、运输和毒性方面的知识鸿沟 人类体内的细菌。阐明Cyps和/或转运蛋白活性降低对BAC毒素的贡献 ICity将使我们能够识别在这些蛋白质中存在遗传变异的高危人群。这个 所获得的知识还可以告知联邦机构制定更适当的暴露限制。这个 该项目的创新之处在于a)通过外源生物实现基因与环境相互作用的新范例-- 加工蛋白质，b)使用综合的肝-肾MPS来评估 外源生物，以及c)用于严格系统毒理学研究的集成组学。