The iron chelator pyridoxal isonicotinoyl hydrazone inhibits mitochondrial lipid peroxidation induced by Fe(II)-citrate.
Pyridoxal isonicotinoyl hydrazone (PIH) is able to prevent iron-mediated hydroxyl radical formation by means of iron chelation and inhibition of redox cycling of the metal. In this study, we investigated the effect of PIH on Fe(II)-citrate-mediated lipid peroxidation and damage to isolated rat liver mitochondria. Lipid peroxidation was quantified by the production of thiobarbituric acid-reactive substances (TBARS) and by antimycin A-insensitive oxygen consumption. PIH at 300 microM induced full protection against 50 microM Fe(II)-citrate-induced loss of mitochondrial transmembrane potential (deltapsi) and mitochondrial swelling. In addition, PIH prevented the Fe(II)-citrate-dependent formation of TBARS and antimycin A-insensitive oxygen consumption. The antioxidant effectiveness of 100 microM PIH (on TBARS formation and mitochondrial swelling) was greater in the presence of 20 or 50 microM Fe(II)-citrate than in the presence of 100 microM Fe(II)-citrate, suggesting that the mechanism of PIH antioxidant action is linked with its Fe(II) chelating property. Finally, PIH increased the rate of Fe(II) autoxidation by sequestering iron from the Fe(II)-citrate complex, forming a Fe(III)-PIH, complex that does not participate in Fenton-type reactions and lipid peroxidation. These results are of pharmacological relevance since PIH is a potential candidate for chelation therapy in diseases related to abnormal intracellular iron distribution and/or iron overload.
Santos
N C
NC
Oxyradical Research Group, Departamento de Biologia Celular, Universidade de Brasília, Brazil.
Castilho
R F
RF
Meinicke
A R
AR
Hermes-Lima
M
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology; D005290:Ferric Compounds / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007501:Iron / Q000737:chemistry; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D002614:Chelating Agents; D005290:Ferric Compounds; D007202:Indicators and Reagents; D007502:Iron Chelating Agents; D017392:Thiobarbituric Acid Reactive Substances; D011730:Pyridoxal; C025314:ferric citrate; C021079:pyridoxal isonicotinoyl hydrazone; D007501:Iron; D007538:Isoniazid