Antioxidant properties of MitoTEMPOL and its hydroxylamine

Jan Trnka,Frances H Blaikie,Angela Logan,Robin A J Smith,Michael P Murphy

doi:10.1080/10715760802582183

Abstract

Piperidine nitroxides such as TEMPOL have been widely used as antioxidants in vitro and in vivo. MitoTEMPOL is a mitochondria-targeted derivative of TEMPOL designed to protect mitochondria from the oxidative damage that they accumulate, but once there is rapidly reduced to its hydroxylamine, MitoTEMPOL-H. As little is known about the antioxidant efficacy of hydroxylamines, this study has assessed the antioxidant activity of both MitoTEMPOL and MitoTEMPOL-H. The hydroxylamine was more effective at preventing lipid-peroxidation than MitoTEMPOL and decreased oxidative damage to mitochondrial DNA caused by menadione. In contrast to MitoTEMPOL, MitoTEMPOL-H has no superoxide dismutase activity and its antioxidant actions are likely to be mediated by hydrogen atom donation. Therefore, even though MitoTEMPOL is rapidly reduced to MitoTEMPOL-H in cells, it remains an effective antioxidant. Furthermore, as TEMPOL is also reduced to a hydroxylamine in vivo, many of its antioxidant effects may also be mediated by its hydroxylamine.

Highlights

Piperidine nitroxides such as TEMPOL (4-hydroxy2,2,6,6-tetramethylpiperidine-1-oxy radical; Figure 1) exhibit potent antioxidant effects in a variety of systems [1Á9]
We found that MitoTEMPOLH was effective at preventing lipid peroxidation and at preventing mitochondrial DNA damage, while the antioxidant activity of MitoTEMPOL was similar to that of TEMPOL
Since piperidine nitroxides are known to be superoxide dismutase (SOD)-mimetics we examined whether superoxide dismutation by TEMPOL was altered by adding an alkylTPP chain

Summary

Introduction

Piperidine nitroxides such as TEMPOL (4-hydroxy2,2,6,6-tetramethylpiperidine-1-oxy radical; Figure 1) exhibit potent antioxidant effects in a variety of systems [1Á9]. For MitoTEMPOL this reduction is so extensive that the nitroxide cannot be detected in respiring mitochondria, suggesting that any antioxidant activity of MitoTEMPOL within mitochondria would be due to its hydroxylamine, MitoTEMPOL-H [18]. Hydroxylamines, including those derived from piperidine nitroxides [15,23Á25] as well as tert-butylhydroxylamine [26,27], have antioxidant properties, the mechanism of these effects has not been studied in detail. Targeting nitroxides to mitochondria is a valid antioxidant strategy, as the hydroxylamine is a potent antioxidant

Methods

Results

Conclusion