title: Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene.
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.
authors.affiliation: Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 21X5, Canada.
authors.forename: Ariel
authors.initials: A
authors.lastname: Revel
authors.forename: Hila
authors.initials: H
authors.lastname: Raanani
authors.forename: Edward
authors.initials: E
authors.lastname: Younglai
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Ian
authors.initials: I
authors.lastname: Rogers
authors.forename: Robin
authors.initials: R
authors.lastname: Han
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Savouret
authors.forename: Robert F
authors.initials: RF
authors.lastname: Casper
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D015153:Blotting, Western; D002452:Cell Count; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004195:Disease Models, Animal; D007124:Immunoenzyme Techniques; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors*; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*
chemical_list: D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D000077185:Resveratrol