Peroxynitrite-derived carbonate and nitrogen dioxide radicals readily react with lipoic and dihydrolipoic acid.
Alpha-lipoic acid (LA) and dihydrolipoic acid (DHLA) may have a role as antioxidants against nitric oxide-derived oxidants. We previously reported that peroxynitrite reacts with LA and DHLA with second-order rate constants of 1400 and 500 M(-1) s(-1), respectively, but indicated that these direct reactions are not fast enough to protect against peroxynitrite-mediated damage in vivo. Moreover, the mechanism of the reaction of peroxynitrite with LA has been recently challenged (J. Biol. Chem.279:9693-9697; 2004). Pulse radiolysis studies indicate that LA and DHLA react with peroxynitrite-derived nitrogen dioxide (*NO2) (k2 = 1.3 x 10(6) and 2.9 x 10(7) M(-1) s(-1), respectively) and carbonate radicals (CO(3-)) (k2 = 1.6 x 10(9) and 1.7 x 10(8) M(-1) s(-1), respectively). Carbonate radical-mediated oxidation of LA led to the formation of the potent one-electron oxidant LA radical cation. LA inhibited peroxynitrite-mediated nitration of tyrosine and of a hydrophobic tyrosine analog, N-t-BOC L-tyrosine tert-butyl ester (BTBE), incorporated into liposomes but enhanced tyrosine dimerization. Moreover, while LA competitively inhibited the direct oxidation of glutathione by peroxynitrite, it was poorly effective against the radical-mediated thiol oxidation. The mechanisms of reaction defined herein allow to rationalize the biochemistry of peroxynitrite based on direct and free radical-mediated processes and contribute to the understanding of the antioxidant actions of LA and DHLA.
Trujillo
Madia
M
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
Folkes
Lisa
L
Bartesaghi
Silvina
S
Kalyanaraman
Balaraman
B
Wardman
Peter
P
Radi
Rafael
R
D000975:Antioxidants / Q000494:pharmacology; D002254:Carbonates / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000737:chemistry / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013696:Temperature; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D014443:Tyrosine / Q000737:chemistry
D000975:Antioxidants; D002254:Carbonates; D005609:Free Radicals; D008081:Liposomes; D013438:Sulfhydryl Compounds; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D014443:Tyrosine; D008063:Thioctic Acid; C015144:dihydrolipoic acid; D009585:Nitrogen Dioxide; D010100:Oxygen