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J. Biol. Chem., Vol. 275, Issue 22, 16702-16708, June 2, 2000

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Ascorbate Is a Potent Antioxidant against Peroxynitrite-induced Oxidation Reactions
EVIDENCE THAT ASCORBATE ACTS BY RE-REDUCING SUBSTRATE RADICALS PRODUCED BY PEROXYNITRITE^*

Michael Kirsch and Herbert de Groot

From the Institut für Physiologische Chemie, Universitätsklinikum, Hufelandstrasse 55, D-45122 Essen, Germany

Peroxynitrite (ONOO/ONOOH) is expected in vivo to react predominantly with CO₂, thereby yielding NO₂^· and CO₃ radicals. We studied the inhibitory effects of ascorbate on both NADH and dihydrorhodamine 123 (DHR) oxidation by peroxynitrite generated in situ from 3-morpholinosydnonimine N-ethylcarbamide (SIN-1). SIN-1 (150 µM)-mediated oxidation of NADH (200 µM) was half-maximally inhibited by low ascorbate concentrations (61-75 µM), both in the absence and presence of CO₂. Control experiments performed with thiols indicated both the very high antioxidative efficiency of ascorbate and that in the presence of CO₂ in situ-generated peroxynitrite exclusively oxidized NADH via the CO₃ radical. This fact is attributed to the formation of peroxynitrate (O₂NOO/O₂NOOH) from reaction of NO₂^· with O₂, which is formed from reaction of CO₃ with NADH. SIN-1 (25 µM)-derived oxidation of DHR was half-maximally inhibited by surprisingly low ascorbate concentrations (6-7 µM), irrespective of the presence of CO₂. Control experiments performed with authentic peroxynitrite revealed that ascorbate was in regard to both thiols and selenocompounds much more effective to protect DHR. The present results demonstrate that ascorbate is highly effective to counteract the oxidizing properties of peroxynitrite in the absence and presence of CO₂ by both terminating CO₃/HO^· reactions and by its repair function. Ascorbate is therefore expected to act intracellulary as a major peroxynitrite antagonist. In addition, a novel, ascorbate-independent protection pathway exists: scavenging of NO₂^· by O₂ to yield O₂NOO, which further decomposes into NO₂ and O₂.

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