The long term goal of this research is to elucidate the mechanisms by which the adrenal steroid dehydroepiandrosterone (DHEA) mediates its pleitropic effects in extrahepatic tissues. DHEA treatment is purported to have numerous beneficial effects in humans, such as lowering risk of cardiovascular disease and lowering body fat. In rodents, low doses of DHEA are chemopreventive, whereas high doses of DHEA lead to peroxisome proliferation and eventually hepatocarcinogenesis. The effects of DHEA are thought to be related to its ability to modulate gene expression. High doses of DHEA increase expression of several hepatic genes including those of the cytochrome P450 monooxygenase 2C and 4A families. The effects of DHEA on expression of these genes in the kidney is not known. Since renal cytochrome P450 monooxygenases of the 4A and 2C families are important in metabolism of arachidonic acid to various vasoactive eicosanoids, modulation of P450s by DHEA may affect basic renal physiological processes, such as maintenance of blood pressure.
The specific aims of the research proposed here are to l) assess the effects of low and high doses of DHEA on renal gene expression, 2) assess the effects of DHEA treatment in a salt-sensitive rat model for hypertension, and 3) assess the effects of low and high doses of DHEA on hepatic and renal expression of a broad range of genes using cDNA array technology. Completion of these aims will help determine how DHEA mediates its pleiotropic effects and allow better determination of benefits and risks of DHEA treatment in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32ES005927-01
Application #
6141607
Study Section
Pathology A Study Section (PTHA)
Program Officer
Shreffler, Carol K
Project Start
2000-05-01
Project End
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$32,416
Indirect Cost
Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
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
Miller, Kristy K Michael; Cai, Jian; Ripp, Sharon L et al. (2004) Stereo- and regioselectivity account for the diversity of dehydroepiandrosterone (DHEA) metabolites produced by liver microsomal cytochromes P450. Drug Metab Dispos 32:305-13
Riddick, David S; Lee, Chunja; Bhathena, Anahita et al. (2004) Transcriptional suppression of cytochrome P450 genes by endogenous and exogenous chemicals. Drug Metab Dispos 32:367-75
Ripp, Sharon L; Falkner, K Cameron; Pendleton, Mary L et al. (2003) Regulation of CYP2C11 by dehydroepiandrosterone and peroxisome proliferators: identification of the negative regulatory region of the gene. Mol Pharmacol 64:113-22
Gu, Shi; Ripp, Sharon L; Prough, Russell A et al. (2003) Dehydroepiandrosterone affects the expression of multiple genes in rat liver including 11 beta-hydroxysteroid dehydrogenase type 1: a cDNA array analysis. Mol Pharmacol 63:722-31
Ripp, Sharon L; Fitzpatrick, Jennifer L; Peters, Jeffrey M et al. (2002) Induction of CYP3A expression by dehydroepiandrosterone: involvement of the pregnane X receptor. Drug Metab Dispos 30:570-5
Fitzpatrick, J L; Ripp, S L; Smith, N B et al. (2001) Metabolism of DHEA by cytochromes P450 in rat and human liver microsomal fractions. Arch Biochem Biophys 389:278-87