Professor

Email Dr. Russell A. Prough
Phone Number: 502-852-7249 (7947)
Fax: 502-852-2660

Address: 580 S. Preston Street, Delia Baxter Building (Baxter II) Room 107
Louisville, KY 40202

Ph.D., Oregon State University

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 (PPARα). 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. We have noted that DHEA may alter the phosphorylation status of PPARα and other nuclear receptors by inducing protein phosphatases, specifically protein phosphatase 2A. This action appears to be different that the action of other peroxisome proliferating agents, and may account for the action of DHEA in inducing PPAR target genes. With Boaz Robinzon, we have also noted that metabolites of DHEA are substrates for the 11β-hydroxysteroid dehydrogenases and are competitive substrates with the glucocorticoids. These enzymes account for the formation of 7α- and 7β-hydroxycholesterol and 7α- and 7β-hydroxy-DHEA and their oxo-derivatives. Our studies have demonstrated a potentially new form of the 11β-HSDs in human liver nuclei which uses NADP+ as cofactor.

Another collaborative project involves the study of aldehyde toxicity in cardiovascular tissues, in conjunction with Aruni Bhatnagar and Daniel Conklin, Medicine/Cardiology. Our project will study the metabolism of acrolein, 4-hydroxynonenal and trans-2-hexenal in vascular tissues and the regulation of these enzymes. In addition, the effects of aldehydes on those cytochromes P450 that metabolize arachidonic acid to various metabolites is understudy to determine whether they affect 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. The role of aldehyde dehydrogenases and glutathione S-transferases in clearance of aldehydes is also understudy, evaluating the various isozymes of this enzyme in mouse and human. The role of these enzyme systems in vascular tissues may be protective against the lipid aldehydes formed during ischemia-reperfusion injury.

Selected Publications

R.N. Hines and R.A. Prough. Amine Oxidases and Reductases, In: Encyclopedia of Drug Metabolism and Interactions, Volume 1, Review of drug metabolism and interactions. Enzyme systems involved in drug metabolism and interactions, (A.D. Rodriguez and M. Sinz, eds.) IN PRESS, John Wiley & Sons, New York, NY (2011)

I. Amunom, S. Srivastava and R.A. Prough, Aldehyde Reduction by Cytochrome P450, In: Current Protocols in Toxicology, In Press, J. Wiley & Sons, New York, NY (2011)

J. Lanceta, R.A. Prough, R. Liang and E. Wang. Impact of MicroRNAs and Their Decanalized Expression During Aging, Special Issue entitled "Epigenetic Mechanisms of Aging and Age-related Diseases. Experimental Gerontology, 45, 269-278 (2010). [PMID: 20034554; PMCID Pending]

D.J. Conklin, O.A. Barski, P. Juvan, T. Rezen, D. Rozman, R.A. Prough, E. Vladykovskaya, S.Q. Liu, S. Srivastava, and A. Bhatnagar. Acrolein Consumption Induces Systemic Dyslipidemia and Lipoprotein Modification, Toxicology and Applied Pharmacology, 243, 1-12 (2010). [PMID: 20034506; PMCID Pending]

D.J. Conklin, P. Haberzettl, R.A. Prough and A. Bhatnagar, Glutathione S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke, American Journal of Physiology - Heart and Circulatory Physiology 296, H1586-H1597 (2009). [PMID: 19270193; PMCID: PMC2685347]

B. Robinzon and R.A. Prough. A Novel NADP+-dependent Dehydrogenase Activity for 7?/? and 11?-Hydroxysteroids in Human Liver Nuclei: A Third 11?-Hydroxysteroid Dehydrogenase, Archives of Biochemistry & Biophysics 486, 170-176 (2009). [PMID: 19416720; PMCID : PMC2742889].

D.J. Conklin, P. Haberzettle, J-F Lesgards, R.A. Prough, S. Srivastava, and A. Bhatnagar, Increased Sensitivity of Glutathione S-Transferase P-null Mice to Cyclophosphamide-induced Urinary Bladder Toxicity, The Journal of Pharmacology & Experimental Therapeutics, 331, 456-69 (2009). [PMID: 19696094; PMCID Pending]

S.J. Webb, K.C. Falkner, T.E. Geoghegan, and R.A. Prough, Convergence of Multiple Nuclear Receptors and Metabolic Signaling Pathways in Xenobiotic and Nutrient Metabolism, In: Volume 2, Cellular and Molecular Toxicology (Ed., Kenneth S. Ramos) of the 2nd Edition of Comprehensive Toxicology (Ed.-Chief, C.A. McQueen), pp. 207-230 Oxford: Academic Press (2010). Elsevier, Oxford, UK (2009).

K.C. Falkner, J.T. Ritter, and R.A. Prough, 'Regulation of the Rat UDP-Glycosyltransferase 1A6 by Glucocorticoids Involving a Cryptic Glucocorticoid Response Element, Drug Metabolism and Disposition, 36, 409-17 (2008) [PMID: 18039810; PMC2423804].

V. Tamasi, K.K. Michael Miller, S.L. Ripp, E. Vila, T.E. Geoghegan, and R.A. Prough, 'Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor Alpha by Dehydroepiandrosterone and Other Peroxisome Proliferators', Molecular Pharmacology 73, 968-76 (2008) [ PMID: 18079279; PMCID pending].

J. Cai, B.G. Hill, A. Bhatnagar, W.M. Pierce, Jr., and R.A. Prough, Bioactivation and Protein Modification Reactions of Unsaturated Aldehydes, In: Advances in Bioactivation Research (A. Elfarra, Ed.), Springer Science+Business Media, New York, NY, Chapter 9, pp. 233-253 (2008).

K.C. Falkner and R.A. Prough, Regulation of the Rat Glutathione S-Transferase A2 Gene by Glucocorticoids: Crosstalk Through C/EBPs, Drug Metabolism Reviews, 39, 371-388 (2007) [PMID: 17786629; PMCID: PMC2423428]

I. Amunom, L.J. Stephens, V. Tamasi, J. Cai, W.M. Pierce, Jr., D.J. Conklin, A. Bhatnagar, S. Srivastava, M.V. Martin, F.P. Guengerich, and R.A. Prough, (2007). Cytochromes P450 Catalyze Oxidation of Alpha,beta-unsaturated Aldehydes. Arch. Biochem. Biophys. 464, 187-196.

K. Kohalmy, V. Tamasi, L. Kobori, E. Sarvary, J.M. Pascussi, P. Porrogi, D. Rozman, R.A. Prough, U.A. Meyer and K. Monostory. (2007). Dehydroepiandrosterone Induces Human CYP2B6 Through the Constitutive Androstane Receptor. Drug Metab Dispos. 35, 1495-1501.

S.J. Webb, K.K. Miller, T.E. Geoghegan, and R.A. Prough (2006). The Biological Actions of Dehydroepiandrosterone Involves Multiple Receptors. Drug Metab Rev. 38, 89-116.

Robinzon,B. and Prough,R.A. (2005). Interactions Between Dehydroepiandrosterone and Glucocorticoid Metabolism in Pig Kidney: Nuclear and Microsomal 11beta-Hydroxysteroid Dehydrogenases. Arch. Biochem. Biophys. 442, 33-40.

Monostory,K., Kohalmy,K., Prough,R.A., Kobori,L., and Vereczkey,L. (2005). The Effect of Synthetic Glucocorticoid, Dexamethasone on CYP1A1 Inducibility in Adult Rat and Human Hepatocytes. FEBS Lett. 579, 229-235.