Role of oxidants in DNA damage. Hydroxyl radical mediates the synergistic DNA damaging effects of asbestos and cigarette smoke.
The mechanism by which cigarette smoking and asbestos exposure synergistically increase the incidence of lung cancer is unknown. We hypothesized that cigarette smoke and asbestos might synergistically increase DNA damage. To test this hypothesis we exposed isolated bacteriophage PM2 DNA to cigarette smoke and/or asbestos, and assessed DNA strand breaks as an index of DNA damage. Our results supported our hypothesis. 78 +/- 12% of the DNA exposed to both cigarette smoke and asbestos developed strand breaks, while only 9.8 +/- 7.0 or 4.3 +/- 3.3% of the DNA exposed to cigarette smoke or asbestos, respectively, developed strand breaks under the conditions of the experiment. Our experimental evidence suggested that cigarette smoke and asbestos synergistically increased DNA damage by stimulating .OH formation. First, significant amounts of .OH were detected by electron paramagnetic resonance (EPR) in DNA mixtures containing both cigarette smoke and asbestos, but no .OH was detected in mixtures containing cigarette smoke alone or asbestos alone. Second, the .OH scavengers, dimethylsulfoxide (DMSO), mannitol, or Na benzoate decreased both .OH detection by EPR and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. Third, the H2O2 scavenger, catalase, and the iron chelators, 1,10-phenanthroline and desferrithiocin, decreased both .OH detection and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. These latter findings suggest that iron contained in asbestos may catalyze the formation of .OH from H2O2 generated by cigarette smoke. In summary, our study indicates that cigarette smoke and asbestos synergistically increase DNA damage and suggests that this synergism may involve .OH production.
Jackson
J H
JH
Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, California 92037.
Schraufstatter
I U
IU
Hyslop
P A
PA
Vosbeck
K
K
Sauerheber
R
R
Weitzman
S A
SA
Cochrane
C G
CG
D001194:Asbestos / Q000494:pharmacology*; D001435:Bacteriophages / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology; D019817:Benzoic Acid; D002374:Catalase / Q000378:metabolism; D004247:DNA / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D006878:Hydroxides; D017665:Hydroxyl Radical; D008353:Mannitol / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010618:Phenanthrolines / Q000494:pharmacology; D012907:Smoking; D013482:Superoxide Dismutase / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
D001565:Benzoates; D004095:Dihydropyridines; D006878:Hydroxides; D010618:Phenanthrolines; D013844:Thiazoles; D001194:Asbestos; D017665:Hydroxyl Radical; D008353:Mannitol; D019817:Benzoic Acid; D004247:DNA; D002374:Catalase; D013482:Superoxide Dismutase; C050223:desferrithiocin; C025205:1,10-phenanthroline; D004121:Dimethyl Sulfoxide