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

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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. Copyright © 2003 John Wiley & Sons, Ltd.