Hepatic drug metabolism in inflammation

在感染或炎症过程中，许多关键药物代谢酶（DME）的表达被破坏。 在肝脏中被抑制，导致药物代谢和清除的改变。这增加了敏感性 肝脏药物不良反应，从而使临床上重要的药物无效或甚至有毒。 DME的基因表达受核受体（NR）超家族成员的调控。然而，在这方面， 肝脏DME在炎症过程中被抑制的确切机制尚未完全了解。 肝脏中的炎症反应由枯否细胞上的Toll样受体（TLR）介导 (KCs)其识别来自受损或应激细胞的微生物组分和内源性配体。这 导致细胞因子的诱导，导致肝细胞中基因表达的抑制。然而，在这方面， TLR也存在于肝细胞上，并且有证据表明肝细胞可以被TLR直接靶向。 来自革兰氏阴性菌的脂多糖（LPS）导致细胞色素P450基因的抑制 表情总的假设是肝细胞中TLR信号通路的激活改变了肝细胞的功能。 通过靶向NR功能从而损害DME，在感染和炎症期间进行药物代谢 表达和活动。为了研究这一假设，提出了以下具体目标。具体 目的1：确定细胞表面受体TLR2和TLR4以及关键的衔接蛋白是否 （TIRAP，TRIP）参与体内DME和NR的调节。具体目标2：确定是否 肝细胞中的TLR信号传导直接参与DME的调节。探索TLR在以下方面的作用： 在体外调节人DME。具体目标3：检查TLR的激活是否会改变 药物、免疫抑制剂、环孢菌素A和抗真菌剂的代谢和毒性， 氯丙嗪这些实验产生的数据将构成一项独立研究的基础 分子药理学专业PI将由Dr. B指导。Moorthy和H博士斯特罗贝尔，谁是 在药理学方面有着良好声誉的研究人员。丰富的智力环境和广泛的资源， 可用于完成这项工作。 了解TLR信号传导在药物代谢调节中的作用将有助于确定TLR的新靶点。 未来的实验操作，以防止炎症介导的药物生物转化的变化。 本研究为TLR基因多态性个体的筛选提供了依据 在新药的临床试验中。

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.