Howard
Glauert,
Ph.D.
Professor

Graduate Center for Nutritional Sciences

Phone:
(859) 257-7789

Fax:
(859) 323-0061

e-mail:
hglauert@uky.edu

Dr. Glauert's laboratory is examining the role of oxidative stress in liver carcinogenesis induced by chemicals such as peroxisome proliferators and PCBs. The mechanisms by which these agents induce or promote carcinogenesis is unclear, but may be related to the induction of cell proliferation, the inhibition of apoptosis, or the production of active oxygen. The production of active oxygen could lead to changes in gene expression in the cell, including the activation of NF-kB and other transcription factors. The peroxisome proliferator ciprofibrate has been found to activate hepatic NF-kB in rats and mice through a mechanism that is mediated by active oxygen. We are currently examining if dietary antioxidants can inhibit NF-kB activation by peroxisome proliferators, and which hepatic cell types have increased NF-kB activation in response to peroxisome proliferators. We also are examining the role of species differences in the activation of NF-kB and other active oxygen-induced transcription factors. For PCBs, we are examining the effect of PCBs on the induction of oxidative DNA damage in the form of 8-hydroxydeoxyguanosine (OHdG); the effect of PCBs on cell proliferation and apoptosis in normal and preneoplastic hepatocytes; and the effect of PCBs on the activation of genes and transcription factors that have previously been shown to be activated, at least in part, by oxidative stress. We have found that PCBs increase the DNA binding activity of the transcription factor NF-kB in rats after either a single administration or multiple administrations over a period of 10 weeks.  The PCB studies are funded by the Superfund Basic Research Program.

Research Publications/Presentations

1.      Tharappel, J.C., E.Y. Lee, L.W. Robertson, B.T. Spear, and H.P. Glauert.  Regulation of cell proliferation, apoptosis, and transcription factor activities during the promotion of liver carcinogenesis by PCBs.  Toxicol. Appl. Pharmacol. 179:172-184, 2002.
 
2.      Fadhel, Z., Z. Lu, L.W. Robertson, and H.P. Glauert.  Effect of 3,3',4,4'-tetrachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl on the induction of hepatic lipid peroxidation and cytochrome P-450 associated enzyme activities in rats.  Toxicology 175:15-25, 2002.
 
3.      OBrien, M.L., M.L. Cunningham, B.T. Spear, and H.P. Glauert.  Peroxisome proliferators do not activate the transcription factors AP-1, early growth response-1 (Egr-1), or heat shock factors 1 and 2 (HSF1/2) in rats or hamsters.  Toxicol. Sci. 69:139-148, 2002.
 
4.      Fischer, J. G., H.P. Glauert, T. Yin, M.L. Sweeney-Reeves, N. Larmonier, and M.C. Black.  Moderate iron overload enhances lipid peroxidation in livers of rats, but does not affect NF-kB activation induced by the peroxisome proliferator, Wy-14,643. J. Nutr. 132:2525-2531, 2002.
 
5.      Calfee-Mason, K.G., B.T. Spear, and H.P. Glauert.  Vitamin E inhibits hepatic NF-kB activation in rats administered the hepatic tumor promoter, phenobarbital.  J. Nutr. 132:3178-3185, 2002.
 
6.      Espandiari, P., H.P. Glauert, H.J. Lehmler, E.Y. Lee, C. Srinivasan, and L.W. Robertson.  Polychlorinated biphenyls (PCBs) as initiators in liver carcinogenesis:  resistant hepatocyte model.  Toxicol. Appl. Pharmacol. 186:55-62, 2003.
 
7.      Lu, Z., J.C. Tharappel, E.Y. Lee, L.W. Robertson, B.T. Spear, and H.P. Glauert.  Effect of a single dose of polychlorinated biphenyls (PCBs) on hepatic cell proliferation and DNA binding activity of NF-kB and AP-1 in rats.  Molec. Carcinog. 37:171-180, 2003.
 
8.      Tharappel, J.C., A. Nalca, A.B. Owens, L. Ghabrial, E.C. Konz, H.P. Glauert, and B.T. Spear.  Cell proliferation and apoptosis are altered in mice deficient in the NF-kB p50 subunit after treatment with the peroxisome proliferator ciprofibrate.  Toxicol. Sci. 75:300-308, 2003.
 
9. Espandiari, P., H.P. Glauert, H.-J. Lehmler, E.Y. Lee, C. Srinivasan and L.W.Robertson. Initiating activity of 4-chlorobiphenyl metabolites in the resistant hepatocyte model.  Toxicol. Sci. 79:41-46, 2004.
 
10. Calfee-Mason, K.G., B.T. Spear, and H.P. Glauert.  Effects of vitamin E on the NF-kB pathway in rats treated with the peroxisome proliferator, ciprofibrate.  Toxicol. Appl. Pharmacol. 199:1-9, 2004.
 
11. Lu, Z., E.Y. Lee, L.W. Robertson, H.P. Glauert, and B.T. Spear.  Effect of 2,2,4,4,5,5-hexachlorobiphenyl (PCB-153) on hepatocyte proliferation and apoptosis in mice deficient in the p50 subunit of the transcription factor NF-kB.  Toxicol. Sci. 81:35-42, 2004.