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Department of Pharmaceutical Sciences and Cancer Center, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado (D.S., D.L.G., D.L.D., D.R.); and Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado (J.Y.H., P.B., L.J.B.)
Experiments using purified recombinant human NAD(P)H:quinone oxidoreductase 1 (NQO1) revealed that the auto-oxidation of fully reduced protein resulted in a 1:1 stoichiometry of oxygen consumption to NADH oxidation with the production of hydrogen peroxide. The rate of auto-oxidation of fully reduced NQO1 was markedly accelerated in the presence of superoxide (
), whereas the addition of superoxide dismutase greatly inhibited the rate of auto-oxidation. The ability of reduced NQO1 to react with suggested a role for NQO1 in scavenging , and this hypothesis was tested using established methods for production and detection. The addition of NQO1 in combination with NAD(P)H resulted in inhibition of dihydroethidium oxidation, pyrogallol auto-oxidation, and elimination of a potassium superoxide-generated ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide: adduct signal (electron spin resonance). Kinetic parameters for the reduction of by NQO1 were estimated using xanthine/xanthine oxidase as the source of and after NQO1-dependent NADH oxidation at 340 nm. The ability of NQO1 to scavenge was also examined using cell sonicates prepared from isogenic cell lines containing no NQO1 activity (NQO1-) or very high levels of NQO1 activity (NQO1+). We demonstrated that addition of NAD(P)H and cell sonicate from NQO1+ but not NQO1- cells resulted in an increased level of scavenging could be inhibited by 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1. NQO1 can generate hydroquinones that are redox active, and the scavenging activity of NQO1 may allow protection against at the site of hydroquinone generation. In addition, the scavenging activity of NQO1 may provide an additional level of protection against induced toxicity.
Address correspondence to: Dr. David Ross, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262. E-mail: david.ross{at}uchsc.edu
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