Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene

J Appl Toxicol. Jul-Aug 2003;23(4):255-61. doi: 10.1002/jat.916.

Abstract

Benzo[a]pyrene (BaP) is an agonistic ligand for the aryl hydrocarbon receptor (AhR) and a major environmental carcinogen implicated in the aetiology of lung cancer through the induction of benzo[a]pyrene diol epoxidation (BPDE) and BPDE-DNA adducts. Because BaP metabolization requires cytochrome P-450 1A1 (CYP1A1) induction through activation of the AhR, we hypothesized that resveratrol, a natural competitive inhibitor of AhR, could prevent these adverse effects of BaP on the lung. Balb-C mice were injected for 5 weeks with corn oil, BaP (5 mg kg(-1) week(-1)), resveratrol (50 mg kg(-1) week(-1)) or BaP + resveratrol. Immunohistochemistry was performed on lung sections for the determination of CYP1A1 protein, BPDE-DNA adducts and apoptosis. A semi-quantitative immunohistochemistry score (H score) was used for data analysis. Mice exposed to BaP had a significant induction of lung BPDE-DNA adducts when compared with controls (H scores: control, 26, interquartile range 18-33; BaP, 276, interquartile range 269-288; P < 0.01). The BPDE-DNA adduct induction by BaP was abrogated significantly by resveratrol (H score: BaP + resveratrol, 103, interquartile range 96-113). A similar pattern was found by immunohistochemistry for apoptosis (H scores: control, 121, interquartile range 102-137; BaP, 288, interquartile range 282-292, P < 0.05; BaP + resveratrol, 132, interquartile range 121-141, P = NS) and CYP1A1 (H scores: control, 170.3, interquartile range 164-175; BaP, 302.3, interquartile range 291-315, P < 0.05; BaP + resveratrol, 200.7, interquartile range 174-215, P = NS). Western blotting confirmed that resveratrol prevented BaP-induced CYP1A1 expression. This increase in CYP1A1 expression in response to BaP administration most likely causes BaP metabolism, BPDE-DNA adduct formation and subsequent apoptosis. All BaP-induced effects could be prevented by resveratrol, suggesting a possible chemopreventive role for this natural phytoalexin against the development of lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Benzo(a)pyrene / metabolism
  • Benzo(a)pyrene / toxicity*
  • Blotting, Western
  • Cell Count
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • DNA Adducts / drug effects
  • DNA Adducts / metabolism
  • DNA Damage / drug effects*
  • Disease Models, Animal
  • Immunoenzyme Techniques
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Aryl Hydrocarbon / antagonists & inhibitors*
  • Resveratrol
  • Stilbenes / therapeutic use*

Substances

  • Anticarcinogenic Agents
  • DNA Adducts
  • Receptors, Aryl Hydrocarbon
  • Stilbenes
  • Benzo(a)pyrene
  • Cytochrome P-450 CYP1A1
  • Resveratrol