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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要苯扎氯铵 (BAC) 广泛用于消毒产品、医疗产品、消费品和食品加工业，表明人类可能会长期暴露在系统中我们的初步研究发现，100 个随机 hu- 中接近 50 个。人类血浆样本中含有可检测水平的 BAC，表明 BAC 确实被吸收了。 COVID-19 大流行导致含 BAC 消毒剂的使用大幅增加，这令人担忧鉴于越来越多的证据表明，由呼吸道、发育、生殖和神经毒性引起的 BAC 和 BAC 诱导的啮齿动物胆固醇和脂质稳态破坏然而，目前还缺乏。我们的目标是了解 BAC 在人类中的代谢、运输和生物学后果。描述 BAC 的代谢和转运途径及其对 BAC 肾毒性的影响。先前对大鼠的研究表明 BAC 会积累到肾毒性的可能性。口服摄入后肾脏中的浓度最高，我们的初步研究表明 BAC 具有强大的细胞毒性- 最近，我们报道了 BAC 是代谢性的。在体外，被人细胞色素 P450 (CYP) 同种型 CYP2D6 和 CYP4 吸收。 BAC 由人体有机阳离子转运蛋白 (hOCT) 主动转运，因为 CYP2D6、CYP4 和 hOCT 具有高度多态性，蛋白质活性差异很大，我们发现 BAC 的毒性肾脏依赖于肝脏和肾脏中 BAC 代谢和转运蛋白质的活动。在目标 1 中，我们将描述 BAC 体外代谢和运输的途径，包括次级代谢途径。通过 β-氧化和葡萄糖醛酸化进行代谢，通过 hOCT、人类多药和毒素挤出亲进行转运在目标 2 中，我们将评估 BAC 在人近曲小管中诱导的肾毒性。 3D 集成肝肾“器官芯片”MPS 中的上皮细胞集成的立体组学、脂质组学和转录组学方法将用于系统评估 BAC 的毒性和生物活性。目标 3，我们将评估 BAC 暴露水平及其与脂质和肾损伤生物标志物的相关性人类，以及遗传变异对 BAC 代谢和处置的影响。该项目的关键在于它将首次解决代谢、运输和毒性方面的知识差距阐明 CYP 和/或转运蛋白活性降低对 BAC 毒性的影响。 icity 将使我们能够识别出这些蛋白质存在遗传变异的高危人群。获得的知识还可以帮助联邦机构制定更适当的暴露限制。该项目的创新在于a）通过外源性基因与环境相互作用的新例子- 处理蛋白质，b) 使用集成的肝肾 MPS 来评估毒理学后果异生素，以及 c) 用于严格系统毒理学研究的综合组学。