Transporter Expression in Response to Hepatotoxicants

对肝毒物反应的转运蛋白表达

• 批准号: 8012480
• 负责人: Jose E Manautou
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012480
• 关键词: Acetaminophen; Acute; Acute Liver Failure; Address; Antioxidants; Biliary; Carbon Tetrachloride; Carrier Proteins; Cell Proliferation; Cell Survival; Cell physiology; Chemical Injury; Chemicals; Clinical; Clinical Management; Data; Development; Disease; Dose; Drug Metabolic Detoxication; Drug toxicity; Enzymes; Event; Excretory function; Exposure to; Functional disorder; Gene Expression; Gene Proteins; Genes; Health; Hepatic; Hepatocyte; Hepatotoxicity; Human; Individual; Inflammation Mediators; Inflammatory; Injury; Injury to Liver; Interleukin-6; Knock-out; Knockout Mice; Knowledge; Kupffer Cells; Laboratories; Lead; Liver; Marketing; Mediating; Mus; Natural regeneration; Nuclear; Oxidative Stress; Oxidative Stress Pathway; P-Glycoproteins; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Poison; Predisposition; Process; Proteins; Reactive Oxygen Species; Recovery; Regimen; Regulation; Research Personnel; Resistance; Rodent; Role; Signal Pathway; Signal Transduction; Source; Testing; Toxic effect; Transcriptional Regulation; Xenobiotics; base; clinically relevant; cytokine; hepatotoxin; inhibitor/antagonist; liver cell proliferation; prevent; programs; protein expression; research study; response; toxicant; transcription factor

Drug toxicity is the number one cause of acute liver failure, and hepatotoxicity is the most common reason why drugs are withdrawn from the US market or are stopped from clinical development. Interestingly, studies in rodents show that the liver acquires resistance to chemical injury following sub-lethal administration of hepatotoxicants such as acetaminophen (APAP) and carbon tetrachloride (CCU). Similar tolerance is seen in a subset of human patients that use APAP. Currently, the mechanism of this resiliency is not known. It likely involves compensatory changes in response to oxidative and inflammatory signals triggered by hepatotoxicant exposure. A better understanding of this phenomenon is important since it may represent a source of clinically relevant drug-disease interactions in individuals with acute liver injury. Changes in transport protein-mediated influx and efflux of xenobiotics could contribute to hepatotoxicant resistance. Preliminary data from this laboratory show significant changes in gene and protein expression for a number of multidrug resistance proteins (Mrps) in mice receiving APAP and CCI4 treatment. We hypothesized that changes in expression of Mrp transporters during chemical-induced liver injury is a compensatory mechanism by which hepatocytes acquire resistance to subsequent hepatotoxicant challenge. We propose to test this hypothesis by first, investigating the temporal and zonal changes in expression and localization of hepatic Mrps following APAP and CCI4 treatment. Then, we will determine if inflammatory mediators contribute to this response by modulating cellular sources of cytokines. The final experiments will examine the role of the transcription factor-E2 p45-related factor 2 (Nrf2) in regulating transporter gene expression in mice lacking Nrf2 during injury and recovery from APAP and CCUtreatment. Nrf2 coordinately regulates the expression of drug metabolizing and detoxification genes. Its role in regulating Mrps has not been investigated. The proposed studies are expected to demonstrate that changes in liver transport protein expression following hepatotoxicant exposure represent an adaptation process that prevents accumulation of certain chemicals. This adaptive response may be essential for hepatocyte survival during periods of injury and regeneration. A comprehensive characterization of transport protein expression under the experimental conditions described in the proposal is of great relevance to human health. This information should give us an indication of the potential susceptibility of individuals with acute liver injury to Pharmaceuticals that: a.) require transporter function for their excretion from the liver, and/or b). generate mediators of inflammation and injury that can be eliminated via transporter action.

药物毒性是急性肝衰竭的第一原因，肝毒性是最常见的原因 为什么要从美国市场撤出药物或停止临床开发。有趣的是， 啮齿动物的研究表明，肝脏在亚致死后获​​得对化学损伤的抗性 肝毒性剂（例如对乙酰氨基酚（APAP）和四氯化碳（CCU））的施用。相似的 在使用APAP的人类患者的一部分中可以看到公差。目前，这种弹性的机制 不知道。它可能涉及响应氧化和炎症信号的补偿性变化 由肝毒性暴露触发。更好地理解这种现象很重要，因为它可能 代表急性肝损伤患者中临床相关的药物疾病相互作用的来源。 转运蛋白介导的异种生物介导的涌入和外排可能有助于肝毒性 反抗。该实验室的初步数据显示基因和蛋白质表达的显着变化 对于接受APAP和CCI4治疗的小鼠中的许多多药抗性蛋白（MRP）。我们 假设化学诱导的肝损伤期间MRP转运蛋白表达的变化是 肝细胞获得对随后的肝毒性挑战的抵抗力的补偿机制。 我们建议首先通过研究表达的时间变化和区域变化来检验这一假设。 APAP和CCI4治疗后肝MRP的定位。然后，我们将确定是否炎症 介质通过调节细胞因子的细胞来源来促进这种反应。最后的实验将 检查转录因子-E2 P45相关因子2（NRF2）在调节转运蛋白基因中的作用 在受伤期间缺乏NRF2的小鼠中表达，并从APAP和CCCUTERATMENT中恢复。 NRF2协调 调节药物代谢和解毒基因的表达。它在调节MRP中的作用尚未 被调查。预计拟议的研究将证明肝脏转运蛋白的变化 肝毒性暴露后的表达代表了防止积累的适应过程 某些化学物质。这种自适应反应对于肝细胞生存可能是必不可少的 伤害和再生。在该下的转运蛋白表达的全面表征 该提案中描述的实验条件与人类健康有很大相关。此信息 应该给我们指示急性肝损伤患者的潜在敏感性 药物：产生 炎症和损伤的介体可以通过转运蛋白作用消除。