Phase I enzymes like CYP1A1 and Phase 2 enzymes such as quinone reductase use NADPH as a reducing co-factor. NADPH, the major cellular source of reducing power, is generated by the pentose-phosphate pathway, which converts glucose-6-phosphate into NADPH and ribose. NADPH, in addition to serving as a cofactor for the enzymes listed above, also serves as a co-factor in the synthesis of reduced glutathione by glutathione reductase. Thus, this pathway is a central pathway in cellular defense against carcinogens and oxidant stress. The key regulator of this pathway, and therefore of NADPH levels, is glucose-6-phosphate dehydrogenase (G6PD). This enzyme has long been thought to be a """"""""housekeeping"""""""" gene that is constitutively expressed. However, recent studies have demonstrated that G6PD is, in fact, highly regulated and inducible. We have investigated changes in G6PD activity and expression in vitro in response to xenobiotics. We found that long-term exposure of cells to the carcinogen benzo[a]pyrene caused an increase in the expression and activity of G6PD. This was not due to modulation of gene transcription, but was due to a post-transcriptional stabilization of G6PD mRNA. We have also found that certain dietary phytochemicals such as dibenzoylmethane and resveratrol increase the expression of G6PD by increasing gene transcription. We are currently examining how this activation occurs. Such increases in G6PD expression would be protective against carcinogens as well as oxidative stress in that it would increase the cell's antioxidant capacity.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC000189-13
Application #
7337774
Study Section
(LM)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Brantley, Eileen; Patel, Vyomesh; Stinson, Sherman F et al. (2005) The antitumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces NF-kappaB activity in drug-sensitive MCF-7 cells. Anticancer Drugs 16:137-43
Dennis, Phillip A; Van Waes, Carter; Gutkind, J Silvio et al. (2005) The biology of tobacco and nicotine: bench to bedside. Cancer Epidemiol Biomarkers Prev 14:764-7
Loaiza-Perez, Andrea I; Kenney, Susan; Boswell, Jamie et al. (2004) Aryl hydrocarbon receptor activation of an antitumor aminoflavone: basis of selective toxicity for MCF-7 breast tumor cells. Mol Cancer Ther 3:715-25
MacDonald, Christopher J; Ciolino, Henry P; Yeh, Grace Chao (2004) The drug salicylamide is an antagonist of the aryl hydrocarbon receptor that inhibits signal transduction induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Res 64:429-34
Ciolino, Henry; MacDonald, Chistopher; Memon, Omar et al. (2003) Dehydroepiandrosterone inhibits the expression of carcinogen-activating enzymes in vivo. Int J Cancer 105:321-5