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toxicity is the number one cause of acute liver failure, and hepatotoxicity is the most common reason why drugs are withdrawn from the US market or are stopped from clinical development.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首要原因，而肝毒性是最常见的原因 为什么药物从美国市场撤回或停止临床开发。有趣的是， 对啮齿动物的研究表明，肝脏在亚致死后获​​得了对化学损伤的抵抗力 服用对乙酰氨基酚（APAP）和四氯化碳（CCU）等肝毒药物。相似的 在使用 APAP 的一部分人类患者中观察到了耐受性。目前，这种弹性机制 尚不清楚。它可能涉及对氧化和炎症信号的反应的代偿性变化 由肝毒物暴露引发。更好地理解这种现象很重要，因为它可能 代表急性肝损伤个体临床相关药物-疾病相互作用的来源。 转运蛋白介导的异生物质流入和流出的变化可能导致肝毒性 反抗。该实验室的初步数据显示基因和蛋白质表达发生显着变化 接受 APAP 和 CCI4 治疗的小鼠体内的多种耐药蛋白 (Mrps)。我们 假设化学物质引起的肝损伤期间 Mrp 转运蛋白表达的变化是 肝细胞获得对随后的肝毒物挑战的抵抗力的补偿机制。 我们建议首先通过研究表达和区域的时间和区域变化来检验这一假设。 APAP 和 CCI4 治疗后肝脏 Mrps 的定位。然后，我们将确定是否有炎症 介质通过调节细胞因子的细胞来源来促进这种反应。最终的实验将 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 缺乏 Nrf2 的小鼠在 APAP 和 CCU 治疗损伤和恢复期间的表达。 Nrf2 坐标 调节药物代谢和解毒基因的表达。其在调节 Mrps 方面的作用尚未 被调查。拟议的研究预计将证明肝脏转运蛋白的变化 肝毒性物质暴露后的表达代表了一种防止积累的适应过程 某些化学品。这种适应性反应可能对于肝细胞在肝细胞存活期间的存活至关重要。 伤害和再生。转运蛋白表达的综合表征 提案中描述的实验条件与人类健康密切相关。此信息 应向我们表明患有急性肝损伤的个体对以下物质的潜在易感性： 药物：a.) 需要转运蛋白功能才能从肝脏排泄，和/或 b)。产生 炎症和损伤的介质可以通过转运蛋白的作用消除。