Hepatic drug metabolism in inflammation

炎症过程中肝脏药物代谢

基本信息

批准号：
7879830
负责人：
Romi Ghose
金额：
$ 5.4万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7879830
关键词：
Adaptor Signaling Protein Attenuated Binding Biological Assay Blood Cell Surface Receptors Cellular Stress Chlorpromazine Clinical Trials Conserved Sequence Cyclosporine Cytochrome P450 Cytosol Data Drug Regulations Drug toxicity EMSA Enzymes Future Gene Expression Genetic Polymorphism Gram-Negative Bacteria Harvest Hepatic Hepatocyte Hepatotoxicity Hour Human Immunosuppressive Agents In Vitro Infection Inflammation Inflammatory Response Interferons Kupffer Cells Ligands Lipopolysaccharides Liver Liver Microsomes MAP Kinase Gene MAP3K7 gene MAPK14 gene MAPK8 gene Mass Spectrum Analysis Measures Mediating Mentors Metabolic Biotransformation Metabolism Molecular Mus Nuclear Receptors Pathway interactions Pharmaceutical Preparations Pharmacology Phosphotransferases Predisposition Proteins RNA Radioimmunoassay Reaction Receptor Gene Receptor Signaling Regulation Research Research Personnel Resources Role Screening procedure Signal Pathway Signal Transduction TBK1 gene TLR2 gene TLR4 gene Time Toll-Like Receptor 2 Toll-like receptors Toxic effect Western Blotting Wild Type Mouse Work base clinically relevant cytokine cytotoxicity drug clearance drug metabolism in vivo inhibiting antibody member microbial novel prevent programs receptor function research study

项目摘要

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-importantmedications 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 intellectualenvironment 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 individualswith polymorphisms in TLR genes during clinical trials of new drugs.

在感染或炎症期间，许多关键药物代谢酶（DME）的表达为抑制肝脏，导致新陈代谢和清除药物的清除。这增加了易感性为了不良肝药物反应，因此使临床上的物质无效甚至有毒。 DME的基因表达受核受体（NR）超家族成员的调节。然而，在炎症期间抑制肝DME的确切机制尚不完全了解。肝脏中的炎症反应是由库普弗细胞上存在的Toll样受体（TLR）介导的（KC）识别受损或应力细胞中的微生物成分和内源性配体。这导致细胞因子诱导，从而导致肝细胞中基因表达的抑制。然而， TLR也存在于肝细胞上，并且有证据表明肝细胞可以直接针对革兰氏阴性细菌的脂多糖（LPS）导致细胞色素P450基因抑制表达。总体假设是肝细胞中TLR信号通路的激活改变了肝通过靶向NR功能，在感染和炎症过程中的药物代谢，从而损害DME 表达和活动。为了研究这一假设，提出了以下特定目标。具体的 AIM 1：确定细胞表面受体TLR2和TLR4以及临界衔接蛋白是否是否（Tirap，Trip）参与体内DME和NRS的调节。特定目标2：确定是否肝细胞中的TLR信号传导直接参与了DME的调节。探索TLR在在体外调节人DME的调节。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和抗抑郁药，氯丙嗪。这些实验产生的数据将构成独立研究的基础分子药理学计划。 PI将由B. Moorthy博士和H. Strobel博士指导，公认的药理学研究人员。丰富的知识环境和广泛的资源是可用于完成这项工作。了解TLR信号在调节药物代谢中的作用将确定新的目标未来的实验操作，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TLR基因中的单个Swith多态性筛查提供基础在新药的临床试验中。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters.

DOI：
10.1016/j.lfs.2011.05.005
发表时间：
2011-07-04
期刊：
LIFE SCIENCES
影响因子：
6.1
作者：
Ghose, Romi;Omoluabi, Ozozoma;Gandhi, Adarsh;Shah, Pranav;Strohacker, Kelley;Carpenter, Katie C.;McFarlin, Brian;Guo, Tao
通讯作者：
Guo, Tao

Regulation of gene expression of hepatic drug metabolizing enzymes and transporters by the Toll-like receptor 2 ligand, lipoteichoic acid.