? 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01DK076057-02
Application #
7351368
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2006-08-22
Project End
2010-07-31
Budget Start
2006-11-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$107,828
Indirect Cost
Name
University of Houston
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
Shah, Pranav; Guo, Tao; Moore, David D et al. (2014) Role of constitutive androstane receptor in Toll-like receptor-mediated regulation of gene expression of hepatic drug-metabolizing enzymes and transporters. Drug Metab Dispos 42:172-81
Gandhi, Adarsh; Guo, Tao; Shah, Pranav et al. (2013) Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice. Toxicol Appl Pharmacol 266:430-8
Gandhi, A S; Guo, T; Shah, P et al. (2012) CYP3A-dependent drug metabolism is reduced in bacterial inflammation in mice. Br J Pharmacol 166:2176-87
Gandhi, Adarsh; Moorthy, Bhagavatula; Ghose, Romi (2012) Drug disposition in pathophysiological conditions. Curr Drug Metab 13:1327-44
Ghose, Romi; Guo, Tao; Vallejo, Jesus G et al. (2011) Differential role of Toll-interleukin 1 receptor domain-containing adaptor protein in Toll-like receptor 2-mediated regulation of gene expression of hepatic cytokines and drug-metabolizing enzymes. Drug Metab Dispos 39:874-81
Ghose, Romi; Omoluabi, Ozozoma; Gandhi, Adarsh et al. (2011) Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. Life Sci 89:57-64
Gandhi, Adarsh; Guo, Tao; Ghose, Romi (2010) Role of c-Jun N-terminal kinase (JNK) in regulating tumor necrosis factor-alpha (TNF-alpha) mediated increase of acetaminophen (APAP) and chlorpromazine (CPZ) toxicity in murine hepatocytes. J Toxicol Sci 35:163-73
Ghose, Romi; Guo, Tao; Haque, Nadia (2009) Regulation of gene expression of hepatic drug metabolizing enzymes and transporters by the Toll-like receptor 2 ligand, lipoteichoic acid. Arch Biochem Biophys 481:123-30
Ghose, Romi; White, Damara; Guo, Tao et al. (2008) Regulation of hepatic drug-metabolizing enzyme genes by Toll-like receptor 4 signaling is independent of Toll-interleukin 1 receptor domain-containing adaptor protein. Drug Metab Dispos 36:95-101