Resveratrol Has Antagonist Activity on the Aryl Hydrocarbon Receptor: Implications for Prevention of Dioxin Toxicity

  1. Robert F. Casper1,1,
  2. Monique Quesne2,
  3. Ian M. Rogers1,
  4. Takuhiko Shirota1,
  5. André Jolivet2,
  6. Edwin Milgrom2 and
  7. Jean-François Savouret2
  1. 1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (R.F.C., I.M.R., T.S.); and 2Institut National de la Santé et de la Recherche Médicale Unit 135, Hôpital de Bicetre, Le Kremlin-Bicêtre, France (M.Q., A.J., E.M., J.-F.S.).

    Abstract

    Aryl hydrocarbon receptor (AhR) ligands such as dioxin and benzo[a]pyrene are environmental contaminants with many adverse health effects, including immunosuppression, carcinogenesis, and endothelial cell damage. We show here that a wine component, resveratrol (3,5,4′-trihydroxystilbene), is a competitive antagonist of dioxin and other AhR ligands. Resveratrol promotes AhR translocation to the nucleus and binding to DNA at dioxin-responsive elements but subsequent transactivation does not take place. Resveratrol inhibits the transactivation of several dioxin-inducible genes including cytochrome P-450 1A1 and interleukin-1β, both ex vivo and in vivo. Resveratrol has adequate potency and nontoxicity to warrant clinical testing as a prophylactic agent against aryl hydrocarbon-induced pathology.

    Footnotes

    • Send reprint requests to: Dr. Jean-François Savouret, Institut National de la Santé et de la Recherche Médicale Unit 135, Hôpital de Bicêtre, 78 rue du Général Leclerc, Le Kremlin-Bicêtre, 94270, France. E-mail:savouret{at}infobiogen.fr

    • ↵1 Current affiliation: Division of Reproductive Sciences, Department of Obstetrics and Gynecology, The University of Toronto, The Toronto Hospital, General Division, Toronto, Ontario, Canada.

    • This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur le Cancer and the Faculté de Médecine Paris-Sud, and the Medical Research Council of Canada. R. F. C. was supported by a joint Medical Research Council of Canada/Institut National de la Santé et de la Recherche Médicale visiting scientist award.

    • Abbreviations:
      AhR
      aryl hydrocarbon receptor
      PAH
      polycyclic aromatic hydrocarbons
      BaP
      benzo[a]pyrene
      TCDD
      2,3,7,8-tetrachlorodibenzo-p-dioxin
      TC[1,6-3H]DD
      2,3,7,8-tetrachloro[1,6-3H]dibenzo-p-dioxin
      DRE
      dioxin responsive element
      CAT
      chloramphenicol acetyl transferase
      TK
      thymidine kinase promoter
      α-NF
      α-naphthoflavone
      NQOR
      NAD(P)H quinone oxidoreductase
      Il-1β
      interleukin-1β
      GFP
      green fluorescent protein
      DMBA
      7,12-dimethylbenzanthracene
      I3C
      indole-3-carbinol
      LTR
      long terminal repeat
      • Received February 8, 1999.
      • Accepted June 22, 1999.
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    1. Molecular Pharmacology October 1, 1999 vol. 56 no. 4 784-790
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