Abstract

We hypothesize that the protective action of DHEA, in part, involves the modulation of the expression of cytochrome P450 monooxygenase(s) and/or other detoxification enzymes required for the bioactivation and disposition of chemicals through both Peroxisome Proliferator Activated Receptor Alpha dependent and independent pathways. Several studies have demonstrated that DHEA ameliorates environmental diseases at dosages lower than those required for DHEA-dependent peroxisome proliferation. The goal of Specific Aim 1 is to establish whether metabolites of DHEA serve as proximal activators of PPAR or other nuclear receptors using cell-based reporter assays. We will test the ability of DHEA metabolites to activate PPAR-alpha, PXR, CAR, LXR, and FXR/BAR using reporter assays. The goal of Specific Aim 2 is to test the hypothesis that 7a-hydroxy-DHEA and 7-oxo-DHEA are formed from DHEA in the hippocampus of rats and to characterize the gene regulation of these enzymes. The effect of DHEA treatment on levels of 7a-hydroxy- and 7-oxo-DHEA in the dentate gyrus region of hippocampus in rats will be determined. The goal of Specific Aim 3 is to test the hypothesis that DHEA treatment activates PPAR by altering PPAR phosphorylation. Therefore, we will test the hypothesis that DHEA activates PPAR by affecting its phosphorylation status in rat hepatocytes and increases its action in transcription. The goal of Specific Aim 4 is to test the hypothesis that the induction of Cyp3all in mouse liver by DHEA treatment is a PXR-dependent process. We will use PPAR-alpha and PXR-null mice to test the hypothesis that induction of Cyp3a11 and other target genes by DHEA is PXR-dependent. The goal of Specific Aim 5 is to test the hypothesis that DHEA induces gene expression through processes other than those mediated by PPAR-alpha and PXR. We will test changes in gene expression after DHEA treatment of wild-type, PPAR -null, and PXR-null mice using a mouse gene array to assess common pathways of regulation of these genes through PPAR, PXR, or unknown signaling pathways. ? ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK054774-05
Application #
6572974
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Margolis, Ronald N
Project Start
1999-03-15
Project End
2006-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$277,279
Indirect Cost

  Institution

Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292

  Publications

Guardiola, John J; Beier, Juliane I; Falkner, K Cameron et al. (2016) Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome. Toxicol Appl Pharmacol 313:47-56
Miller, Kristy K Michael; Al-Rayyan, Numan; Ivanova, Margarita M et al. (2013) DHEA metabolites activate estrogen receptors alpha and beta. Steroids 78:15-25
Robinzon, B; Prough, R A (2009) A novel NADP(+)-dependent dehydrogenase activity for 7alpha/beta- and 11beta-hydroxysteroids in human liver nuclei: A third 11beta-hydroxysteroid dehydrogenase. Arch Biochem Biophys 486:170-6
Falkner, K C; Ritter, J K; Prough, R A (2008) Regulation of the rat UGT1A6 by glucocorticoids involves a cryptic glucocorticoid response element. Drug Metab Dispos 36:409-17
Tamasi, Viola; Miller, Kristy K Michael; Ripp, Sharon L et al. (2008) Modulation of receptor phosphorylation contributes to activation of peroxisome proliferator activated receptor alpha by dehydroepiandrosterone and other peroxisome proliferators. Mol Pharmacol 73:968-76
Kohalmy, Krisztina; Tamasi, Viola; Kobori, Laszlo et al. (2007) Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor. Drug Metab Dispos 35:1495-501
Falkner, K Cameron; Prough, Russell A (2007) Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: crosstalk through C/EBPs. Drug Metab Rev 39:401-18
Bertrand, C A; Laboisse, C; Hopfer, U et al. (2006) Methods for detecting internalized, FM 1-43 stained particles in epithelial cells and monolayers. Biophys J 91:3872-83
Webb, Stephanie J; Geoghegan, Thomas E; Prough, Russell A et al. (2006) The biological actions of dehydroepiandrosterone involves multiple receptors. Drug Metab Rev 38:89-116
Robinzon, Boaz; Prough, Russell A (2005) Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: nuclear and microsomal 11beta-hydroxysteroid dehydrogenases. Arch Biochem Biophys 442:33-40

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