Department of Biochemistry and Molecular Biology

Assistant Professor

Ph.D., University of Louisville, 1994

Research Interests: Mechanism of action of dehydroepiandrosterone (DHEA

Dr. Webb’s research is focused on understanding the mechanism of action of dehydroepiandrosterone (DHEA). DHEA is a naturally occurring steroid in humans and is the precursor to the sex steroids. Circulating levels of DHEA, which are maximal in early adulthood, steadily decline with age. Administration of DHEA to rodent models has many purported beneficial effects including anti-aging, anti-diabetic, anti-cancer, and anti-atherogenic properties. The underlying mechanisms of DHEA action are not understood. DHEA belongs to a class of chemicals that regulate a profile of genes characteristic in peroxisome proliferation. DHEA induces peroxisome proliferation through the PPAR, although DHEA is not a ligand of the receptor, and appears to have regulatory functions independent of PPAR. Global gene array analysis of expression of rat hepatic genes, performed by Dr. Tom Geoghegan, revealed that DHEA induces the expression of the insulin-like growth factor binding protein-1 (IGFBP-1) by 4.9 fold. IGFBP-1 is synthesized in the liver and secreted into the circulation where it exerts counter-regulatory effects on glucose metabolism by modulating bioavailability and action of insulin-like growth factor I (IGF-I). Increased IGFBP-1 leads to a decrease in bioavailable IGF-I. IGF-I is important in acute glucose metabolism, cell proliferation and differentiation. Ablation of the GH/IGF-1 axis in GHR -/- mice leads to increased life span. IGF-1 expression is elevated in certain cancers, including colon cancer. DHEA induced expression of IGFBP-1 leading to a decrease in bioavailable IGF-1 may, in part, explain DHEA’s anti-diabetic, anti-cancer and anti-aging properties. Research in the lab is focused on DHEA regulation of IGFBP-1 and other proteins involved in IGF-1 action, and whether DHEA regulation of IGFBP-1 involves the PPAR and PXR nuclear hormone receptors.

Selected Publications

1. Oral administration of 2-Amino-1-6-phenylimidazo[4,5-b]pyridine (PhIP) yields PhIP-DNA adducts but not tumors in male Syrian hamsters congenic at the N-acetyltransferase 2 (NAT2) locus. A.J. Fretland, U.S. Devanaboyina, Y. Feng, M.A. Leff, G.H. Xiao, S.J. Webb, and D.W. Hein. Toxicol Sci. 59 (2), 226-30 (2001).
   
2. DNA adduct levels and absence of tumors in female rapid and slow acetylator congenic hamsters administered the rat mammary carcinogen 2-amino-1-methyl-6-phenylimidazo{4,5-b]pyridine (PhIP). A.J. Fretland, U.-S. Devanaboyina, N.A. Nanju, M.A. Leff, G.H. Xiao, S.J. Webb, and D.W. Hein. J. Biochem Mol 15 (1), 26-33 (2001).
   
3. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphism. D.W. Hein, M.A. Doll, A.J. Fretland, M.A. Leff, S.J. Webb, G.H. Xiao, U.-S. Devanaboyina, and N.J. Nanju. Cancer Epi. Bio. & Prev. 9, 29-42 (2000).
   
4. Caspase-mediated cleavage of APC results in an amino-terminal fragment with an intact armadillo repeat domain. S.J. Webb, D. Nicholson, J. Bubb, A.H. Wyllie. FASEB J. 13 (2), 339-346 (1999).
   
5. Apoptosis and carcinogenesis. A.H. Wyllie, C.O.C. Bellamy, V.J. Bubb, A.R. Clarke, S. Corbet, L. Curtis, D.J. Harrison, M.L. Hooper, N. Toft, S. Webb, and C.C. Bird. Brit. J. of Cancer 80 (Supp. 1), 34-37 (1998).
   
6. Modulated expression of cytochrome P450 mRNAs by dehydroepiandrosterone, nafenopin, and triiodothyronine. D.W. Singleton, X-.D. Lei, S.J. Webb, R.A. Prough, and T.E. Geoghegan. Drug Metab. and Disp. 27 (2), 193-200 (1999).
   
7. Regulation of CYP4A expression in rat by dehydroepiandrosterone and thyroid hormone. S.J. Webb, G.-H. Xiao, T.E. Geoghegan and R.A. Prough, Molecular Pharmacology 49, 267-287 (1996).
   
8. "Regulation of Cytochromes P450 by DHEA and Its Anticarcinogenic Action," R.A. Prough, X.-D. Lei, G.-H. Xiao, H.-Q. Wu, T.E. Geoghegan, and S.J. Webb, In: Dehydroepiandrosterone (DHEA) and Aging, Annals of the New York Academy of Sciences 774, 187-199 (1995).
   
9. Induction of microsomal and peroxisomal enzymes by dehydroepiandrosterone and its reduced metabolites in rats. R.A. Prough, S.J. Webb, H.Q. Wu, D.P. Lapenson, and D.J. Waxman, Cancer Research 54, 2878-2886 (1994).