Hepatic drug metabolism in inflammation

炎症过程中肝脏药物代谢

• 批准号: 7351368
• 负责人: Romi Ghose
• 金额: $ 10.78万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-22 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351368
• 关键词: biological signal transduction; chlorpromazine; cyclosporines; cytotoxicity; drug metabolism; enzyme activity; gel mobility shift assay; genetically modified animals; infection; inflammation; laboratory mouse; liver cells; liver pharmacology; mass spectrometry; nuclear receptors; polymerase chain reaction; radioimmunoassay; receptor expression; toll like receptor; western blottings

DESCRIPTION (provided by applicant): During infection or inflammation, the expression of many key drug metabolizing enzymes (DMEs) is suppressed in the liver, leading to altered metabolism and clearance of drugs. This increases the susceptibility to adverse hepatic drug reactions, thus rendering clinically-important medications ineffective or even toxic. The gene expression of DMEs is regulated by members of the nuclear receptor (NR) superfamily. However, the exact mechanism by which hepatic DMEs are suppressed during inflammation is not fully understood. Inflammatory responses in the liver are mediated by Toll-like receptors (TLRs) present on Kupffer cells (KCs) which recognize microbial components and endogenous ligands from damaged or stressed cells. This results in the induction of cytokines, leading to suppression of gene expression in hepatocytes. However, TLRs are also present on hepatocytes, and there is evidence that hepatocytes can be directly targeted by lipopolysaccharide (LPS) from gram negative bacteria resulting in suppression of Cytochrome P450 gene expression. The overall hypothesis is that activation of TLR signaling pathways in hepatocytes alters hepatic drug metabolism during infection and inflammation by targeting NR function and thereby impairing DME expression and activity. To investigate this hypothesis, the following Specific Aims are proposed. Specific Aim 1: Determine whether the cell surface receptors, TLR2 and TLR4 and the critical adaptor proteins (TIRAP, TRIP), are involved in regulation of DMEs and NRs in vivo. Specific Aim 2: Determine whether TLR signaling in the hepatocytes are directly involved in regulation of DMEs. Explore the role of TLRs in regulation of human DMEs in vitro. Specific Aim 3: Examine whether activation of TLRs will alter the metabolism and toxicity of the drugs, the immunosuppressant, Cyclosporin A, and the anti-depressant, Chlorpromazine. The data generated from these experiments will form the basis of an independent research program in Molecular Pharmacology. The PI will be mentored by Dr. B. Moorthy and Dr. H. Strobel, who are well-established investigators in Pharmacology. A rich intellectual environment and extensive resources are available for completion of this work. Understanding the role of TLR signaling in regulation of drug metabolism will identify novel targets for future experimental manipulations to prevent inflammation-mediated alterations in drug biotransformation. Finally, these studies will provide a basis for screening of individuals with polymorphisms in TLR genes during clinical trials of new drugs.

描述（由申请人提供）： 在感染或炎症过程中，许多关键药物代谢酶（DME）的表达在肝脏中受到抑制，从而导致代谢改变和药物清除。这增加了对不良肝药物反应的敏感性，从而使临床上重要的药物无效甚至有毒。 DME的基因表达受核受体（NR）超家族成员的调节。但是，在炎症期间抑制肝DME的确切机制尚未完全了解。肝脏中的炎症反应是由kupffer细胞（KC）上存在的Toll样受体（TLR）介导的，这些受体（KC）识别受损或压力细胞的微生物成分和内源性配体。这会导致细胞因子诱导，从而导致肝细胞中基因表达的抑制。然而，肝细胞上也存在TLR，并且有证据表明肝细胞可以通过革兰氏阴性细菌直接靶向脂多糖（LPS），从而导致细胞色素P450基因表达抑制。总体假设是，肝细胞中TLR信号通路的激活通过靶向NR功能，从而改变了感染和炎症期间肝药物代谢，从而改变了DME表达和活性。为了研究这一假设，提出了以下特定目标。具体目标1：确定细胞表面受体TLR2和TLR4以及临界衔接蛋白（TIRAP，TRIP）是否参与体内DME和NRS的调节。具体目标2：确定肝细胞中的TLR信号是否直接参与了DME的调节。探索TLR在体外调节人DMES中的作用。特定目的3：检查TLR的激活是否会改变药物的代谢和毒性，免疫抑制剂，环孢菌素A和抗抑制剂，氯丙胺。这些实验产生的数据将构成分子药理学独立研究计划的基础。 PI将由B. Moorthy博士和H. Strobel博士指导，他们是药理学领域良好的研究人员。可以完成丰富的智力环境和广泛的资源。 了解TLR信号在调节药物代谢中的作用将确定未来实验操作的新目标，以防止炎症介导的药物生物转化的改变。最后，这些研究将为筛查新药临床试验期间TLR基因中具有多态性的个体的基础。