Oxidant Generation Resulting from the Interaction of Copper with Menadione (Vitamin K3)-a Model for Metal-mediated Oxidant Generation in Living Systems.

The oxidation of hydroquinones is of interest both due to the generation of reactive oxygen species (ROS) and to the implications to trace metal redox state. Menadione (MNQ), a typical toxicant quinone used extensively for studying the mechanisms underlying oxidative stress, is known to be an effective source of exogenous ROS. In this study, the kinetics and mechanism of the oxidation of menadiol (MNH2 Q, the reduced form of MNQ) in the absence and presence of copper (Cu) over the pH range 6.0-7.5 was examined. The autoxidation rate increased with increasing pH and concentration of O2 and also slightly increased with increasing concentration of MNH2 Q and MNQ with Cu shown to play a significant role in catalysing the oxidation of MNH2 Q. A kinetic model showed that the mono-deprotonated menadiol, MNHQ- , accounted for the pH dependence of the autoxidation rate. In this proposed mechanism, both MNH2 Q and MNHQ- species were oxidized quickly by Cu(II), generating menadione semiquinone (MNSQ•- ) and superoxide (O2 •- ) and the reduced form of Cu, Cu(I). Oxygen not only facilitated the catalytic role of Cu(II) by rapidly regenerating Cu(II) but also effectively removed MSNQ•- , generating the important chain-propagating species O2 •- . The model demonstrated that Cu(I) was a significant sink of O2 •- resulting in the generation of H2 O2 with subsequent generation of highly oxidative intermediates including Cu(III). These results provide considerable insight into the clinical significance of the biological activation and detoxification of MNQ with the kinetic model developed of use in identifying key processes in the generation of harmful oxidants in living systems.