title: Oxidant-dependent metabolic activation of polycyclic aromatic hydrocarbons by phorbol ester-stimulated human polymorphonuclear leukocytes: possible link between inflammation and cancer.
abstract: Oxidants, such as those generated by metabolically activated phagocytes in inflammation, have been implicated in the metabolic activation of carcinogens, and in this study we demonstrate that the interaction of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP 7,8-dihydrodiol) with phorbol ester-stimulated polymorphonuclear leukocytes (PMNs) results in the generation of both a chemiluminescent intermediate and one that covalently binds to DNA. Cu(II)(3,5-diisopropylsalicylic acid)2 (CuDIPS), a biomimetic superoxide dismutase, and azide, a myeloperoxidase inhibitor, inhibited both of these reactions, indicating a dependency on oxygen-derived oxidants in these hydrocarbon-activation processes. Concordant with the formation of a carcinogen-DNA adduct, the admixture of BP 7,8-dihydrodiol and phorbol ester-stimulated PMNs elicited mutagenesis in Salmonella typhimurium strain TA100. 7,8-Dihydro-BP and BP cis-7,8-dihydrodiol were also mutagenic, whereas derivatives lacking a double bond at the 9,10 position were not. These results demonstrate that oxidants generated by metabolically stimulated PMNs can activate penultimate polycyclic aromatic hydrocarbons to a genotoxic metabolite and further defines a role for inflammation in carcinogenesis.
authors.forename: M A
authors.initials: MA
authors.lastname: Trush
authors.forename: J L
authors.initials: JL
authors.lastname: Seed
authors.forename: T W
authors.initials: TW
authors.lastname: Kensler
mesh_terms: D001386:Azides / Q000494:pharmacology; D001580:Benzopyrenes / Q000378:metabolism*; D001711:Biotransformation; D004247:DNA / Q000378:metabolism; D004101:Dihydroxydihydrobenzopyrenes; D006801:Humans; D007249:Inflammation; D008163:Luminescent Measurements; D009154:Mutation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors; D012459:Salicylates / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D001386:Azides; D001580:Benzopyrenes; D004101:Dihydroxydihydrobenzopyrenes; D012459:Salicylates; D013481:Superoxides; C017228:benzo(a)pyrene 7,8-dihydrodiol; C030865:copper bis(3,5-diisopropylsalicylate); D004247:DNA; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate