title: Effect of phytochemical intervention on dibenzo[a,l]pyrene-induced DNA adduct formation.
abstract: Dibenzo[a,l]pyrene (DBP) has been found to be the most potent carcinogen of the polycyclic aromatic hydrocarbons (PAHs). Primary sources for DBP in the environment are combustion of wood and coal burning, gasoline and diesel exhaust, and tires. Given the likelihood of environmental exposure to DBP and strong experimental evidence of its potency, it is likely to contribute to lung cancer development. Intervention with compounds of natural origin ("phytochemicals") is considered an effective means to prevent cancer development and favorably modulate the underlying mechanisms, including DNA adduct formation. In this study, several agents have been identified that inhibit environmental carcinogen-induced DNA adduct formation using a cell-free microsomal system. Of the ten agents tested, resveratrol (648 ± 26 adducts/10(9) nucleotides), oltipraz (1007 ± 348 adducts/10(9) nucleotides), delphinidin (1252 ± 142 adducts/10(9) nucleotides), tanshinone I (1981 ± 213 adducts/10(9) nucleotides), tanshinone IIA (2606 ± 478 adducts/10(9) nucleotides) and diindoylmethane (3643 ± 469 adducts/10(9) nucleotides) were the most effective compared to vehicle treatment (14,062 ± 1097 adducts/10(9) nucleotides). DBP is metabolized by phase I metabolizing enzymes CYP1A1, CYP1A2, and CYP1B1. DBP-induced DNA adducts can be inhibited by several mechanisms. We found that all the test agents inhibited DNA adducts by inhibiting one or more of these enzymes. Oltipraz inhibited DNA adducts entirely by inhibiting the CYP450s, while resveratrol and delphinidin inhibited DNA adducts by also interacting directly with the carcinogenic metabolite, anti-dibenzo(a,l)pyrene-11,12-dihydrodiol-13,14-epoxide.
authors: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States.
authors: Gilandra K
authors: GK
authors: Russell
authors: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, United States; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, United States.
authors: Ramesh C
authors: RC
authors: Gupta
authors: James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, United States. Electronic address: mvvadh01@louisville.edu.
authors: Manicka V
authors: MV
authors: Vadhanam
mesh_terms: D045784:Abietanes / Q000494:pharmacology; D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology; D001580:Benzopyrenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D064209:Phytochemicals / Q000494:pharmacology*; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D045784:Abietanes; D000872:Anthocyanins; D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D007211:Indoles; D064209:Phytochemicals; D013267:Stilbenes; C021751:tanshinone; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; C017185:delphinidin; C041517:dibenzo(a,l)pyrene; D000077185:Resveratrol; C016392:3,3'-diindolylmethane
keywords: (32)P-postlabeling; Cytochrome P450; DNA adducts; Dibenzo[a,l]pyrene; Polycyclic aromatic hydrocarbons