ABSTRACT
Alberto Boveris, Silvia Alvarez, Silvia Lores Arnaiz, and Laura B. Valdez School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
I. INTRODUCTION Peroxynitrite (ONOO−) is an oxidizing and nitrating species produced in vivo both as an intracellular and as an extracellular metabolite in mammals. On the one hand, it is formed in isolated mitochondria (1,2), which indicates the physiological intracellular generation of this species, considering that isolated mitochondria have been recognized as effective sources of nitric oxide (NO) (3) and superoxide anion (O2−) (4) under physiological conditions. On the other hand, a series of cell types, such as macrophages (5), neutrophils (6), Kupffer cells (7), and cultured endothelial cells (8) produce ONOO− vectorially into the extracellular space. In both cases, peroxynitrite is formed in the intracellular and the extracellular spaces through the diffusion-controlled reaction (k = 1.9 × 1010 M−1s−1) of NO and O2− (9). This free radical termination reaction-both reactants have one unpaired electron in their external orbitals-was proposed 10 years ago by Beckman as the molecular mechanism of ischemic injury (10), and it is now also recognized as the main pathway of intramitochondrial NO utilization (1) and as one of the molecular strategies that are responsible for the cytotoxicity of specialized cells (5-7). At physiological pH, ONOO− protonates to yield peroxynitrous acid (ONOOH; pKa = 6.8), which rearranges itself to yield nitrate (NO3−) or to decompose, producing radical species such as hydroxyl radical (HO·) and nitric dioxide (NO2·), with a global half-life for ONOO− of about 1 s (11,12).
