My research program focuses on how genes that encode foreign compound metabolizing enzymes are regulated at the molecular level. The studies focus on metabolism of aldehydic products of volatile organic compounds, sterols, and polychlorinated hydrocarbons. Specifically, we are addressing the regulation of these genes through action of nuclear receptors such as AhR, CAR, PXR, LXR, and FXR, as well as other transcription factors such as Nrf2 and AP-1. Many aldehyde metabolizing enzymes are regulated through action of the reactive processes of the aldehydes themselves on nuclear receptors, serving as electrophilic metabolites. The studies continue with our ongoing collaboration with Aruni Bhatnagar, Daniel Conklin, and Sanjay Srivastava in Cardiology, Department of Medicine. Currently, I am working with Matthew Cave in the Division of Gastroenterology looking at how PCBs alter intermediary metabolism through the nuclear receptors that utilize bile acids as ligands (PXR, LXR, FXR). The work over the past 30 years allows my program to assess effects of obesity on the expression and regulation of genes encoding foreign compound metabolizing enzymes. A third study is focused upon a new human gene of the 11β-hydroxysteroid dehydrogenases that Boaz Robinzon, Hebrew University, Jerusalem, and I discovered in human liver nuclei and microsomes that catalyzes the oxidation of glucocortoids by NADP+. This gene is not expressed in rodents. We are expressing the gene product in E. coli and characterizing its biochemical properties related to organell localization in the human hepatocyte and its substrate specificity. We are also studying its expression during the obese state, in collaboration with Stephen Winters, M.D., Division of Endocrinology, Department of Medicine.
Amy Illick - Lab Technician
Tracy Kruer PhD - Postdoctoral Fellow
- Regulation of the rat UDP-glycosyltransferase 1A6 by glucocorticoids involving a cryptic glucocorticoid response element, K.C. Falkner, J.T. Ritter, and R. A. Prough, Drug Metabolism and Disposition, 36, 409-17 (2008) [PMID: 18039810; PMCID PMC2423804].
- "Modulation of receptor phosphorylation contributes to activation of peroxisome proliferator activated receptor alpha by dehydroepiandrosterone and other peroxisome proliferators", V. Tamasi, K.K. Michael Miller, S.L. Ripp, E. Vila, T.E. Geoghegan, and R.A. Prough, Molecular Pharmacology 73, 968-76 (2008) [ PMID: 18079279; PMCID PMC2423814].
- "Glutathione S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke", D.J. Conklin, P. Haberzettl, R.A. Prough and A. Bhatnagar, American Journal of Physiology - Heart and Circulatory Physiology 296, H1586-H1597 (2009). [PMID: 19270193; PMCID: PMC2685347]
- "A novel NADP+-dependent dehydrogenase activity for 7α/β and 11β-hydroxysteroids in human liver nuclei: A third 11β-hydroxysteroid dehydrogenase", B. Robinzon and R.A. Prough, Archives of Biochemistry & Biophysics 486, 170-176 (2009). [PMID: 19416720; PMCID : PMC2742889]
- "Increased sensitivity of glutathione S-transferase P-null mice to cyclophosphamide-induced urinary bladder toxicity" D.J. Conklin, P. Haberzettle, J-F Lesgards, R.A. Prough, S. Srivastava, and A. Bhatnagar, The Journal of Pharmacology & Experimental Therapeutics, 331, 456-69 (2009). [PMID: 19696094; PMCID: PMC2775270]
- "Acrolein consumption induces systemic dyslipidemia and lipoprotein modification" 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 Toxicology and Applied Pharmacology, 243, 1-12 (2010). [PMID: 20034506; PMCID: PMC2922677]
- "MicroRNA group disorganization in aging", J. Lanceta, R.A. Prough, R. Liang and E. Wang, Special Issue entitled "Epigenetic Mechanisms of Aging and Age-related Diseases. Experimental Gerontology, 45, 269-278 (2010). [PMID: 20034554; PMCID Pending]
- "Convergence of Multiple Nuclear Receptors Signaling", S.J. Webb, K.C. Falkner, T.E. Geoghegan, and R.A. Prough, In: Charlene A. McQueen, Comprehensive Toxicology, Volume 2, pp. 207–230 Oxford: Academic Press (2010).
- "Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s", V. Tamasi, K. Monostory, R.A. Prough, and A. Falus, Cellular and Molecular Life Sciences, 68, 1131–1146 (2011). [PMID: 21184128; PMCID Pending]
- Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation" N.L. Makia, P.Bojang., K.C. Falkner, D.J. Conklin, and R.A. Prough, Chemico-biological Interactions, 191, 278-287 (2011) [PMID: 21256123; PMCID Pending]
- Aldehyde reduction by cytochrome P450", I. Amunom, S. Srivastava and R.A. Prough, In: Current Protocols in Toxicology, Chapter 4, Unit 4.37, J. Wiley & Sons, New York, NY (2011).[ PMID:21553396; PMCID: PMCID:PMC3110767]
- Cytochromes P450s catalyze the reduction of α,β-unsaturated lipid aldehydes", I. Amunom, L.J. Dieters, V. Tamasi, J. Cai, D.J. Conklin, S. Srivastava, M.V. Martin, F.P. Guengerich, and R.A. Prough, Chemical Research in Toxicology, 24,1223-30 (2011) [PMID: 21766881; PMCID:PMC3180908]
- "Acrolein-induced dyslipidemia and acute-phase response are independent of HMG-CoA reductase", D.J.Conklin, R.A. Prough, P. Juvan,