Augusto Ohara, Trindade Daniel F, Linares Edlaine, Vaz Sandra M
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
An Acad Bras Cienc. 2008 Mar;80(1):179-89. doi: 10.1590/s0001-37652008000100013.
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.
Tempol（4-羟基-2,2,6,6-四甲基-1-哌啶氮氧自由基）及相关环状氮氧化物作为抗氧化剂具有巨大的治疗潜力，这激发了无数关于它们与活性氧反应的研究。相比之下，氮氧化物与一氧化氮衍生的氧化剂的反应研究较少。然而，这一点很重要，因为tempol也已被证明能保护动物免受与炎症相关的损伤，炎症的特征是一氧化氮及其衍生的氧化剂产量增加。在此，我们综述了近期关于环状氮氧化物减轻一氧化氮衍生氧化剂毒性机制的研究。例如，我们展示了tempol保护小鼠免受对乙酰氨基酚诱导的肝毒性的数据，并讨论了可能的保护机制。鉴于总结的研究，有人提出氮氧化物在炎症条件下减轻组织损伤主要是因为它们能够与二氧化氮和碳酸根自由基快速反应。在此过程中，氮氧化物被氧化为相应的氧化铵阳离子，并可通过与上游物质（如过氧亚硝酸根和过氧化氢）或细胞还原剂反应，再循环回氮氧化物。一种辅助保护机制可能是诱导型一氧化氮合酶表达的下调。文中还探讨了这些机制可能的治疗意义。
