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）： 在感染或炎症期间，肝脏中许多关键药物代谢酶 (DME) 的表达受到抑制，导致药物代谢和清除发生改变。这增加了对肝脏药物不良反应的敏感性，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。然而，炎症过程中肝脏 DME 被抑制的确切机制尚不完全清楚。肝脏的炎症反应是由库普弗细胞 (KC) 上的 Toll 样受体 (TLR) 介导的，该受体可识别受损​​或应激细胞中的微生物成分和内源性配体。这会导致细胞因子的诱导，从而抑制肝细胞中的基因表达。然而，TLR 也存在于肝细胞上，并且有证据表明肝细胞可以直接被革兰氏阴性菌的脂多糖 (LPS) 靶向，从而抑制细胞色素 P450 基因表达。总体假设是，肝细胞中 TLR 信号通路的激活通过靶向 NR 功能来改变感染和炎症期间的肝脏药物代谢，从而损害 DME 表达和活性。为了研究这一假设，提出了以下具体目标。具体目标 1：确定细胞表面受体 TLR2 和 TLR4 以及关键接头蛋白（TIRAP、TRIP）是否参与体内 DME 和 NR 的调节。具体目标 2：确定肝细胞中的 TLR 信号传导是否直接参与 DME 的调节。探索 TLR 在体外调节人类 DME 中的作用。具体目标 3：检查 TLR 的激活是否会改变药物、免疫抑制剂环孢素 A 和抗抑郁药氯丙嗪的代谢和毒性。这些实验产生的数据将构成分子药理学独立研究项目的基础。 PI 将由 B. Moorthy 博士和 H. Strobel 博士指导，他们是药理学领域的知名研究人员。这项工作的完成有丰富的智力环境和广泛的资源。 了解 TLR 信号传导在药物代谢调节中的作用将为未来的实验操作确定新的靶标，以防止药物生物转化中炎症介导的改变。最后，这些研究将为新药临床试验中筛选TLR基因多态性个体提供依据。