Numerous studies have demonstrated that a variety of dietary constituents inhibit chemically induced tumorigenesis in rodents, including DMBA induced mammary tumors. The many steps between exposure to a procarcinogen and the transformation of a normal cell into a cancer cell begin with the activation of the procarcinogen to genotoxic forms. For the aryl hydrocarbons (AH), this process is initiated by the AH receptor (AhR), a cytosolic transcription factor. Natural endogenous or exogenous ligands of the AhR have been postulated but remain, for the most part, unidentified. We identified several dietary polyphenolic compounds that are natural ligands of the AhR. We found curcumin is a ligand of the AhR and an inhibitor of cytochrome, P450 1A1, in MCF-7 human breast cancer cells. Diosmin and diosmetin are agonists of the AhR, causing an increase in CYP1A1 mRNA. We further found that diosmetin, but not diosmin, was inhibitory to CYP1A1 activity. The result was that diosmetin inhibited adduct formation and DMBA induced cytotoxicity, while diosmin stimulated both parameters. The flavonoid galangin is an inhibitor of DMBA metabolism and an agonist/antagonist of the AhR in MCF-7 cells. The dietary flavonols, quercetin and kaempferol, are ligands of the AhR that differentially affect CYP1A1 transcription. We recently found that the steroid hormone, dehydroepiandrosterone, inhibits CYP1A1 expression by a post-transcriptional mechanism. We examined the effect of resveratrol on CYP1A1 enzyme activity and expression in human hepatoma cells and found resverotrol inhibited the induced CYP1A1 activity by B[a]P and TCDD in a dose-dependent manner in human breast and liver cancer cells. The AhR also regulates the transcription of a number of Phase II enzymes. The effect of detoxification mechanisms by dietary flavonoids are under our current investigation.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC000155-11
Application #
6557518
Study Section
(BRL)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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