Nitric oxide synergistically enhances DNA strand breakage induced by polyhydroxyaromatic compounds, but inhibits that induced by the Fenton reaction.
Reactive oxygen and nitrogen species play an important role in many human diseases including cancer. We have found that incubation of pBR322 plasmid DNA with a nitric oxide (NO)-releasing compound such as diethylamine NONOate and a polyhydroxyaromatic compound such as catechol, 1,4-hydroquinone, or pyrogallol caused synergistic induction of single-strand breakage, whereas either compound alone induced much less breakage. Phenol, resorcinol, or guaiacol (O-methylcatechol) did not exhibit this synergistic effect of DNA damage with NO. The strand breakage induced by NO with pyrogallol was prevented by excess superoxide dismutase, carboxy-PTIO (an NO-trapping agent), or anti-oxidants (urate, ascorbate). Possible mechanisms for the induction of this synergistic effect of NO and polyhydroxyaromatic compounds on the strand breakage are proposed, including involvement of peroxynitrite formed from NO and O2.- derived from autooxidation of polyhydroxyaromatics. This pathway for generation of reactive species from NO and catechol-type compounds (e.g., L-dopa, catechol-estrogen) may be important in many pathological conditions, because both compounds are concurrently formed or present in vivo. On the other hand, NO dose-dependently inhibited the strand breakage mediated by 1,4-hydroquinone plus Cu2+ or Fenton reaction (H2O2, iron or copper). This inhibition could be due to formation of a complex between NO and a metal ion, inhibiting generation of reactive species from H2O2. Our results can account for contrasting activities of NO reported in relation to tissue injury. NO can play both detrimental and beneficial roles in DNA damage, depending on the type and amounts of reactive oxygen species and metal ions concurrently present.
Yoshie
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Y
Unit of Endogenous Cancer Risk Factors, International Agency for Research on Cancer, Lyon, France.
Ohshima
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H
D002396:Catechols / Q000494:pharmacology; D003300:Copper; D004249:DNA Damage; D004357:Drug Synergism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006873:Hydroquinones / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D010957:Plasmids / Q000187:drug effects; D017382:Reactive Oxygen Species
D002396:Catechols; C045076:Fenton's reagent; D006873:Hydroquinones; D009566:Nitrates; D017382:Reactive Oxygen Species; C039642:peroxynitric acid; D009569:Nitric Oxide; C002385:linsidomine; D003300:Copper; D006861:Hydrogen Peroxide; D008981:Molsidomine; D007501:Iron; C034221:catechol