Our laboratory has been characterizing bioactivation of carcinogens in the prostate, a tissue with limited cytochrome P450 activity. This proposal is based on our identification of a novel molecular target for nutrients in the prostate, which is a protein that oxidizes prostate carcinogens to DNA-reactive metabolites. We have discovered that several important nutrients, in particular, ferulic acid, vanillic acid and epigallocatechin gallate, are effective and potent inhibitors of this enzyme. Thus, by inhibiting this highly specific target and blocking the activation of prostate carcinogens, nutrients display chemopreventative activity, cDNA clones of the target protein have been obtained and cells overexpressing the oxidase characterized. Four major genotoxic chemicals have been identified that induce prostate tumors when administered to rodents: 3,2'-dimethyl-4-aminobiphenyl (DMAB), 2-amino-l-methyl-6-phenyl-imidazo(4,5- b)pyridine (PhIP), N-nitrosobis (2-oxopropyl) amine and N-methyl-nitrosourea. PhIP is a heterocyclic amine produced during cooking that has only recently been identified as a prostate carcinogen, while DMAB, a synthetic aromatic amine, is a member of a large family of aminobiphenyls synthesized by the chemical dye industry. We hypothesize that dietary nutrients alter prostate carcinogen metabolism by blocking the activity of the novel oxidase that activates these compounds. To test this hypothesis, the ability of our novel oxidase activity to metabolize DMAB will be evaluated. We will also assess the effects of dietary nutrients on this enzyme activity in prostate cells. These studies will provide important information on a unique target for chemopreventative agents in the prostate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100994-03
Application #
6916503
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Kim, Young Shin
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$303,490
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Black, Adrienne T; Gordon, Marion K; Heck, Diane E et al. (2011) UVB light regulates expression of antioxidants and inflammatory mediators in human corneal epithelial cells. Biochem Pharmacol 81:873-80
Black, Adrienne T; Hayden, Patrick J; Casillas, Robert P et al. (2011) Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide. Toxicol Appl Pharmacol 253:112-20
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Black, Adrienne T; Hayden, Patrick J; Casillas, Robert P et al. (2010) Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide. Toxicol Appl Pharmacol 249:178-87
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Shakarjian, Michael P; Heck, Diane E; Gray, Joshua P et al. (2010) Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure. Toxicol Sci 114:5-19
Jan, Yi-Hua; Heck, Diane E; Gray, Joshua P et al. (2010) Selective targeting of selenocysteine in thioredoxin reductase by the half mustard 2-chloroethyl ethyl sulfide in lung epithelial cells. Chem Res Toxicol 23:1045-53
Black, Adrienne T; Joseph, Laurie B; Casillas, Robert P et al. (2010) Role of MAP kinases in regulating expression of antioxidants and inflammatory mediators in mouse keratinocytes following exposure to the half mustard, 2-chloroethyl ethyl sulfide. Toxicol Appl Pharmacol 245:352-60

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