Russell A. Prough, Ph.D.
Professor of Biochemistry & Molecular Biology
Room 720 (office); Room 716 (lab); Bldg. 55A
Office: (502) 852-7249
Fax: (502) 852-6222
Regulation of genes encoding enzymes of foreign compound metabolism
The research pursued in Dr. Prough's laboratory focuses on the study of the mechanism of modulation of the enzyme activity of various drug/carcinogen metabolizing enzymes by various steroid hormones and sterols. For example, Tom Geoghegan and I are studying the effect of dehydroepiandrosterone (DHEA) and its metabolites on regulation of the cytochromes P450; DHEA and DHEA sulfate are major circulating sterols in humans and some primates (5-10 µM concentration). DHEA is also a peroxisome proliferator, but regulates other enzyme systems in addition to those regulated by the peroxisome proliferator activated receptor alpha (PPARa). PPAR and other members of subfamily III of the steroid hormone receptors may interact and modulate their respective action as mediators of the process of gene expression. Studies on rat CYP3A23 suggest that DHEA or a metabolite apparently regulate this gene, most likely through the action of the pregnane X receptor (PXR) and constitutive androgen receptor (CAR). The role of metabolites of DHEA on activation of PPARa, ERa/ß, CAR and PXR are under study. A new research area related to DHEA and these enzymes is how aging effects the responsiveness of the genes of foreign compound metabolism to exogenous and endogenous chemicals which alters their gene expression. Preliminary and anecdotal data would indicate that the responsiveness of old animals is significantly less than young animals. Another collaborative project involves the study of aldehyde toxicity in cardiovascular tissues, in conjunction with Aruni Bhatnagar, Sumanth Prahbu, Sanjay Srivastava, and Stanley D'Souza. My project will study the metabolism of acrolein and trans-2-hexenal in vascular tissues and the regulation of these enzymes. Dan Conklin and I are working on the effects of these aldehydes on vascular smooth muscle and endothelial cells, particularly the effects of these aldehydes on foreign compound metabolizing enzymes. In addition, the effects of aldehydes on those cytochromes P450 that metabolize arachidonic acid to various metabolites affecting vasoactive action and proliferation/development of vascular smooth muscle and endothelial cells. Aldehydes serve as both substrates for some of these hemoproteins, as well as mechanism-based inactivators of CYP function.
- "Glucocorticoids inhibit interconversion of 7-hydroxy- and 7-oxo- metabolites of dehydroepiandrosterone (DHEA): A role for 11b-hydroxysteroid dehydrogenases?", B. Robinzon, K.K. Michael, S.L. Ripp, and R.A. Prough, Archive of Biochemistry and Biophysics 412, 251-258 (2003).
- "Dehydroepandrosterone Affects the Expression of 11ß-HSD1 mRNA in Rat Liver: a cDNA Array Analysis", S. Gu, S.L.Ripp, R.A. Prough and T.E. Geoghegan, Molecular Pharmacology 63, 722-731(2003).
- "Negative Regulation of CYP2C11 by DHEA and Peroxisome Proliferators: Identification of the Negative Regulatory Region of the Gene", S.L. Ripp, K.C. Falkner, M.L. Pendleton, V. Tamasi, and R.A. Prough, Molecular Pharmacology 64, 13-22 (2003).
- "Stereo- and Regioselectivity Account for the Diversity of DHEA Metabolites Produced by Liver Microsomal Cytochromes P450", K.K. Michael Miller, J. Cai, S.L. Ripp, W.M. Pierce, Jr., T.H. Rushmore, and R.A. Prough, Drug Metabolism and Disposition 32, 305-313, (2004).
- "Regulation of NAD(P)H:quininone Oxidoreductase by Glucocorticoids", J.A. Pinaire, G.-H. Xiao, K.C. Falkner, and R.A. Prough, Toxicology and Applied Pharmacology 195, IN PRESS (2004).