Hepatic drug metabolism in inflammation

在感染或炎症过程中，许多关键的药物代谢酶(DME)的表达是 在肝脏中被抑制，导致新陈代谢和药物清除的改变。这增加了敏感度 对肝脏药物的不良反应，从而使临床上重要的药物无效，甚至有毒。 DMES的基因表达受核受体超家族成员的调控。然而， 肝脏DME在炎症过程中被抑制的确切机制尚不完全清楚。 肝脏炎症反应是由枯否细胞上的Toll样受体(TLRs)介导的 (KCS)识别受损或应激细胞中的微生物成分和内源配体。这 结果诱导细胞因子，导致肝细胞基因表达受抑。然而， TLRs也存在于肝细胞上，有证据表明肝细胞可以直接通过 革兰氏阴性菌脂多糖抑制细胞色素P450基因 表情。总的假设是肝细胞中TLR信号通路的激活改变了肝脏 通过靶向NR功能从而损害DME在感染和炎症过程中的药物代谢 表情和活动。为了研究这一假设，提出了以下具体目标。特定的 目的1：测定细胞表面受体TLR2、TLR4和关键接头蛋白 (TIRAP，TRIP)，参与体内DMES和NRS的调节。具体目标2：确定是否 肝细胞中的TLR信号直接参与DMES的调节。探索TLRs在以下方面的作用 体外对人DMES的调节。具体目标3：检查TLRs的激活是否会改变 药物的代谢和毒性，免疫抑制剂，环孢素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 分子药理学专业。PI将由B.Moorthy博士和H.Strobel博士指导，他们是 药理学方面的资深研究人员。丰富的智力环境和丰富的资源是 可用于完成这项工作。 了解TLR信号在药物代谢调节中的作用将确定新的靶点 未来的实验操作，以防止炎症介导的改变药物的生物转化。 这些研究将为筛选TLR基因多态个体提供依据 在新药的临床试验期间。

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.