DNA strand scission and free radical production in menadione-treated cells. Correlation with cytotoxicity and role of NADPH quinone acceptor oxidoreductase.
Menadione (MD; 2-methyl-1,4-naphthoquinone), a redox cycling quinone was shown to induce single (ss)- and double (ds)-strand DNA breaks in human MCF-7 cells. This DNA damage was mediated via the hydroxyl radical as evidenced by electron spin resonance spectroscopy (ESR) studies utilizing the spin trap, 5,5-dimethyl-1-pyrroline-1-oxide. The free radical production and DNA damage were shown to play a role in MD cytotoxicity as revealed by the reversal of MD toxicity and inhibition of hydroxyl radical production by exogenously added catalase. The role of NADPH quinone acceptor oxidoreductase in the metabolism of MD was evaluated. Purified quinone acceptor oxidoreductase in combination with MD resulted in the production of significant levels of the hydroxyl radical as measured by ESR. Dicumarol, an inhibitor of quinone acceptor oxidoreductase, decreased the production of the hydroxyl radical and attenuated DNA strand breaks in MCF-7 cells treated with MD.
Department of Pharmacology, University of Minnesota, Minneapolis 55455.
L M
LM
Nutter
E O
EO
Ngo
G R
GR
Fisher
P L
PL
Gutierrez
D002374:Catalase / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000378:metabolism; D004247:DNA / Q000187:drug effects*; D001728:Dicumarol / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D013057:Spectrum Analysis; D014812:Vitamin K / Q000378:metabolism / Q000633:toxicity*
D003497:Cyclic N-Oxides; D005609:Free Radicals; D014812:Vitamin K; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D001728:Dicumarol; D004247:DNA; D002374:Catalase; D016660:NAD(P)H Dehydrogenase (Quinone)