TY - JOUR
T1 - Kinetics of the reaction between nitroxide and thiyl radicals
T2 - Nitroxides as antioxidants in the presence of thiols
AU - Goldstein, Sara
AU - Samuni, Amram
AU - Merenyi, Gabor
PY - 2008/9/18
Y1 - 2008/9/18
N2 - Cyclic nitroxides effectively protect cells, tissues, isolated organs, and laboratory animals from radical-induced damage. The present study focuses on the kinetics and mechanisms of the reactions of piperidine and pyrrolidine nitroxides with thiyl radicals, which are involved in free radical "repair" equilibria, but being strong oxidants can also produce cell damage. Thiyl radicals derived from glutathione, cysteine, and penicillamine were generated in water by pulse radiolysis, and the rate constants of their reactions with 2,2,6,6-tetramethylpip-eridine-1-oxyl (TPO), 4-OH-TPO, and 3-carbamoyl-proxyl were determined to be (5-7) × 108 M -1 s_1 at pH 5-7, independent of the structure of the nitroxide and the thiyl radical. It is suggested that the reaction of nitroxide (>NO) with thiyl radical (RS) yields an unstable adduct (> NOSR). The deprotonated form of this adduct decomposes via heterolysis of the N-O bond, yielding the respective amine (>NH) and sulfinic acid (RS(O)OH). The protonated form of the adduct decomposes via homolysis of the N-O bond, forming the aminium radical (>NH+) and sulfinyl radical (RSO), which by subsequent reactions involving thiol and nitroxide produce the respective amine and sulfonic acid (RS(O)2OH). Nitroxides that are oxidized to the respective oxoammonium cations (> N+=O) are recovered in the presence of NADH but not in the presence of thiols. This suggests that the reaction of >N+=0 with thiols yields the respective amine. Two alternative mechanisms are suggested, where >N+=O reacts with thiolate (RS-) directly generating the adduct >NOSR or indirectly forming >NO and RS, which subsequently together yield the adduct >NOSR. Under physiological conditions the adduct is mainly deprotonated, and therefore nitroxides can detoxify thiyl radicals. The proposed mechanism can account for the protective effect of nitroxides against reactive oxygen- and nitrogen-derived species in the presence of thiols.
AB - Cyclic nitroxides effectively protect cells, tissues, isolated organs, and laboratory animals from radical-induced damage. The present study focuses on the kinetics and mechanisms of the reactions of piperidine and pyrrolidine nitroxides with thiyl radicals, which are involved in free radical "repair" equilibria, but being strong oxidants can also produce cell damage. Thiyl radicals derived from glutathione, cysteine, and penicillamine were generated in water by pulse radiolysis, and the rate constants of their reactions with 2,2,6,6-tetramethylpip-eridine-1-oxyl (TPO), 4-OH-TPO, and 3-carbamoyl-proxyl were determined to be (5-7) × 108 M -1 s_1 at pH 5-7, independent of the structure of the nitroxide and the thiyl radical. It is suggested that the reaction of nitroxide (>NO) with thiyl radical (RS) yields an unstable adduct (> NOSR). The deprotonated form of this adduct decomposes via heterolysis of the N-O bond, yielding the respective amine (>NH) and sulfinic acid (RS(O)OH). The protonated form of the adduct decomposes via homolysis of the N-O bond, forming the aminium radical (>NH+) and sulfinyl radical (RSO), which by subsequent reactions involving thiol and nitroxide produce the respective amine and sulfonic acid (RS(O)2OH). Nitroxides that are oxidized to the respective oxoammonium cations (> N+=O) are recovered in the presence of NADH but not in the presence of thiols. This suggests that the reaction of >N+=0 with thiols yields the respective amine. Two alternative mechanisms are suggested, where >N+=O reacts with thiolate (RS-) directly generating the adduct >NOSR or indirectly forming >NO and RS, which subsequently together yield the adduct >NOSR. Under physiological conditions the adduct is mainly deprotonated, and therefore nitroxides can detoxify thiyl radicals. The proposed mechanism can account for the protective effect of nitroxides against reactive oxygen- and nitrogen-derived species in the presence of thiols.
UR - http://www.scopus.com/inward/record.url?scp=53049108906&partnerID=8YFLogxK
U2 - 10.1021/jp804743g
DO - 10.1021/jp804743g
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C2 - 18729428
AN - SCOPUS:53049108906
SN - 1089-5639
VL - 112
SP - 8600
EP - 8605
JO - Journal of Physical Chemistry A
JF - Journal of Physical Chemistry A
IS - 37
ER -