Oxidant-dependent metabolic activation of polycyclic aromatic hydrocarbons by phorbol ester-stimulated human polymorphonuclear leukocytes: possible link between inflammation and cancer.
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.
Trush
M A
MA
Seed
J L
JL
Kensler
T W
TW
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
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