Menadiol

Abstract: Living cells typically contain numerous redox couples such as NAD+/NADH, NADP+/NADPH, cystine/cysteine, and the oxidized and reduced forms of glutathione and metalloenzymes. It is expected that the intracellular concentrations of these couples may change selectively with changes in the cellular environment, such as those due to hormones, growth factors, and nutrients. The present work employs an electrochemical potentiometric means of probing intracellular redox activity in live cells. The couple menadione/menadiol is used as a carrier mediator, carrying electrons across the cell membrane, and sensing intracellular redox enzyme activity. The extracellular menadiol redox activity is monitored by means of an extracellular solution containing the ferricyanide/ferrocyanide couple and a gold electrode. Evidence is presented that the extracellular rate of reduction of ferricyanide is limited by the intracellular rate of reduction of menadione. A substantial fraction (30−80% depending on cell type) of ferricyani...

Abstract: The cytotoxic properties of quinones, such as menadione, are mediated through one electron reduction to yield semi-quinone radicals which can subsequently enter redox cycles with molecular oxygen leading to the formation of reactive oxygen radicals. In this study the role of reduction and oxidation in the toxicity of mitoxantrone was studied and its toxicity compared with that of adriamycin and menadione. The acute toxicity of mitoxantrone was not mediated through one-electron reduction, since inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells against oxidative damage, did not affect its toxicity. Adriamycin was the most potent inhibitor of protein and RNA synthesis of the three quinones. Menadione, at concentrations up to 25 microM, did not inhibit either protein or RNA synthesis unless dicoumarol, an inhibitor of DT-diaphorase, was also present. The two-electron reduction of menadione by DT-diaphorase is therefore a protective mechanism in the cell. This enzyme also protected against the toxicity of high concentrations (100 microM) of mitoxantrone. The inhibitory effect of mitoxantrone, but not of menadione or adriamycin, on cell growth was prevented by inhibiting the activity of cytochrome P450-dependent mixed function oxidase (MFO) system using metyrapone. This suggests that mitoxantrone is oxidised to a toxic intermediate by the MFO system.