Metabolism and Cytotoxicity of Menadione and Its Metabolite in Rat Platelets

Abstract

Previous studies suggest that menadione is cytotoxic to rat platelets by oxidative stress. In order to elucidate the mechanism of this toxicity, metabolism of menadione and the cytotoxicity of a metabolite, menadione-glutathione conjugate (MEN-SG), were investigated in platelet rich plasma and washed platelet (WP) systems. When menadione was incubated in platelets, the primary metabolite was MEN-SG, which was excreted into the incubation medium. Incubation of subcellular fractions of platelets with synthetic MEN-SG led to increases in oxygen consumption that were similar to the parent compound, menadione. However, unlike menadione, exposure of MEN-SG to intact platelets in WP system neither resulted in increased oxygen consumption nor induced cell lysis as measured by lactate dehydrogenase leakage. In contrast to menadione, levels of MEN-SG in the incubation medium were unaffected by the presence of platelets, suggesting that MEN-SG was not consumed (or taken up) by platelets. These results indicate that even though MEN-SG was able to induce oxidative stress within platelets as potently as menadione itself, the MEN-SG formation from menadione in platelets appeared not to contribute to menadione's cytotoxicity. This lack of MEN-SG toxicity was likely due to its rapid excretion outside the cells.