Mechanism-based inhibition of thioredoxin reductase by antitumor quinoid compounds.

摘要: Quinoids undergo metabolism by a number of flavoenzymes. Reactive species formed during the some quinoids might be anticipated to inhibit flavoenzyme activity. Several have been tested for their ability rat liver thioredoxin reductase (TR). The antitumor quinones diaziquone and doxorubicin, quinoneimine 2,6-dichloroindophenol, were found inhibitors reduction 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) TR. inhibition was most marked after incubation quinoid with NADPH enzyme 60 min before adding DTNB, Ki values 0.5 microM diaziquone, 0.07 2,6-dichloroindophenol. three all produced time-dependent first order loss TR There formation electron spin resonance-detectable semiquinoid free radicals upon doxorubicin 2,6-dichloroindophenol under anaerobic conditions. Oxygen redox cycling did not make major contribution quinoids, as shown absence significant reversal conditions lack effect oxygen radical scavengers dimethyl sulfoxide, superoxide dismutase catalase. It possible demonstrate NADPH-dependent covalent binding radiolabeled or apoprotein. is that bind noncovalently apoprotein, FAD prosthetic group. results study suggest are mechanism-based showing metabolism- irreversible