Abstract
The substantial therapeutic potential of tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy) and related cyclic nitroxides as antioxidants has stimulated innumerous studies of their reactions with reactive oxygen species. In comparison, reactions of nitroxides with nitric oxide-derived oxidants have been less frequently investigated. Nevertheless, this is relevant because tempol has also been shown to protect animals from injuries associated with inflammatory conditions, which are characterized by the increased production of nitric oxide and its derived oxidants. Here, we review recent studies addressing the mechanisms by which cyclic nitroxides attenuate the toxicity of nitric oxide derived oxidants. As an example, we present data showing that tempol protects mice from acetaminophen-induced hepatotoxicity and discuss the possible protection mechanism. In view of the summarized studies, it is proposed that nitroxides attenuate tissue injury under inflammatory conditions mainly because of their ability to react rapidly with nitrogen dioxide and carbonate radical. In the process the nitroxides are oxidized to the corresponding oxammonium cation, which, in turn, can be recycled back to the nitroxides by reacting with upstream species, such as peroxynitrite and hydrogen peroxide, or with cellular reductants. An auxiliary protection mechanism may be down-regulation of inducible nitric oxide synthase expression. The possible therapeutic implications of these mechanisms are addressed.
Highlights
In spite of the substantial evidence indicating that oxidative mechanisms contribute to the pathogenesis of many human diseases, multiple large prospective intervention trials with classical antioxidants, such as vitamin C, vitamin E and β-carotene, failed to have a significant impact upon disease risk and progression (Brennan and Hazen 2003, Kris-Etherton et al 2004)
Our results indicated that tempol worsened L. amazonensis infection by a dual mechanism involving down-regulation of induced nitric oxide synthase (iNOS) expression and scavenging of nitric oxide-derived oxidants (Linares et al in press)
As we observed in the case of mice infected with L. amazonensis (Linares et al in press), the predominant form of tempol appears to be the hydroxylamine because of the reducing physiological environment (Linares et al in press)
Summary
In spite of the substantial evidence indicating that oxidative mechanisms contribute to the pathogenesis of many human diseases, multiple large prospective intervention trials with classical antioxidants, such as vitamin C, vitamin E and β-carotene, failed to have a significant impact upon disease risk and progression (Brennan and Hazen 2003, Kris-Etherton et al 2004). Nitroxides are multifunctional antioxidants because of their ability to react with diverse biological oxidants and reductants while being recycled through oxammonium cation- (TPNO+) and hydroxylamine-derivatives (TPNOH), respectively (Fig. 1).
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