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.
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Authors | M A Trush, J L Seed, T W Kensler |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 82
Issue 15
Pg. 5194-8
(Aug 1985)
ISSN: 0027-8424 [Print] United States |
PMID | 2991910
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Azides
- Benzopyrenes
- Dihydroxydihydrobenzopyrenes
- Salicylates
- Superoxides
- benzo(a)pyrene 7,8-dihydrodiol
- copper bis(3,5-diisopropylsalicylate)
- DNA
- Peroxidase
- Tetradecanoylphorbol Acetate
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Topics |
- Azides
(pharmacology)
- Benzopyrenes
(metabolism)
- Biotransformation
- DNA
(metabolism)
- Dihydroxydihydrobenzopyrenes
- Humans
- Inflammation
- Luminescent Measurements
- Mutation
- Neutrophils
(drug effects, metabolism)
- Oxidation-Reduction
- Peroxidase
(antagonists & inhibitors)
- Salicylates
(pharmacology)
- Superoxides
(metabolism)
- Tetradecanoylphorbol Acetate
(pharmacology)
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