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Hepatic drug metabolism in inflammation

炎症过程中肝脏药物代谢

基本信息

批准号：
7656687
负责人：
Romi Ghose
金额：
$ 12.53万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-22 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7656687
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 Environment Enzymes Future Gene Expression Genetic Polymorphism Gram-Negative Bacteria Harvest Hepatic Hepatocyte Hepatotoxicity Hour Human Immunosuppressive Agents In Vitro Individual 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

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）：