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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Aryl Hydrocarbon-Induced Cytochrome P-450 1A1 Enzyme Activity and CYP1A1 Expression by Resveratrol

Henry P. Ciolino and Grace Chao Yeh
Molecular Pharmacology October 1999, 56 (4) 760-767;
Henry P. Ciolino
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Grace Chao Yeh
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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

  • 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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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

Inhibition of Aryl Hydrocarbon-Induced Cytochrome P-450 1A1 Enzyme Activity and CYP1A1 Expression by Resveratrol

Henry P. Ciolino and Grace Chao Yeh
Molecular Pharmacology October 1, 1999, 56 (4) 760-767;

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Research ArticleArticle

Inhibition of Aryl Hydrocarbon-Induced Cytochrome P-450 1A1 Enzyme Activity and CYP1A1 Expression by Resveratrol

Henry P. Ciolino and Grace Chao Yeh
Molecular Pharmacology October 1, 1999, 56 (4) 760-767;
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