Abstract
We investigated the effect of resveratrol, a constituent of the human diet that has been shown to inhibit aryl hydrocarbon-induced carcinogenesis in animals, on the carcinogen activation pathway regulated by the aryl hydrocarbon receptor. Resveratrol inhibited the metabolism of the environmental aryl hydrocarbon benzo[a]pyrene (B[a]P) catalyzed by microsomes isolated from B[a]P-treated human hepatoma HepG2 cells. Resveratrol competitively inhibited, in a concentration-dependent manner, the activity of the carcinogen activating enzymes cytochrome P-450 (CYP)1A1/CYP1A2 in microsomes and intact HepG2 cells. Resveratrol inhibited the B[a]P-induced expression of the CYP1A1gene, as measured at the mRNA and transcriptional levels. Resveratrol abolished the binding of B[a]P-activated nuclear aryl hydrocarbon receptor to the xenobiotic-responsive element of theCYP1A1 promoter but did not itself bind to the receptor. Resveratrol was also effective in inhibiting CYP1A1transcription induced by the aryl hydrocarbon dimethylbenz[a]anthracene in human mammary carcinoma MCF-7 cells. These data demonstrate that resveratrol inhibits aryl hydrocarbon-induced CYP1A activity in vitro by directly inhibiting CYP1A1/1A2 enzyme activity and by inhibiting the signal transduction pathway that up-regulates the expression of carcinogen activating enzymes. These activities may be an important part of the chemopreventive activity of resveratrol in vivo.
Footnotes
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Send reprint requests to: Dr. Henry P. Ciolino, Basic Research Laboratory, Building 560/Room 12-05, National Cancer Institute-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, MD 21702-1201. E-mail:hciolino{at}mail.ncifcrf.gov
- Abbreviations:
- AH
- aryl hydrocarbon
- AHR
- aryl hydrocarbon receptor
- B[a]P
- benzo[a]pyrene
- CAT
- chloramphenicol acetyltransferase
- CYP
- cytochrome P-450
- DMBA
- dimethylbenz[a]anthracene
- DTT
- dithiothreitol
- EMSA
- electrophoretic mobility shift assay
- EROD
- ethoxyresorufin-O-deethylase
- ETRF
- ethoxyresorufin
- β-Gal
- β-galactosidase
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- poly(dI/dC)
- poly(deoxyinosinic/deoxycytidylic acid)
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- TBE
- Tris/borate/EDTA
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- XRE
- xenobiotic responsive element
- Received March 31, 1999.
- Accepted July 11, 1999.
- U.S. Government
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