The role of oxidative stress in the toxicity of pyridoxal isonicotinoyl hydrazone (PIH) analogues.
Pyridoxal isonicotinoyl hydrazone (PIH) analogues are effective iron chelators in vivo and in vitro, and may be of value for the treatment of secondary iron overload. The sensitivity of Jurkat cells to Fe-chelator complexes was enhanced several-fold by the depletion of the antioxidant glutathione, indicating the role of oxidative stress in their toxicity. K562 cells loaded with eicosapentaenoic acid, a fatty acid particularly susceptible to oxidation, were also more sensitive to the toxic effects of the Fe complexes, and toxicity was proportional to lipid peroxidation. Thus Fe-chelator complexes cause oxidative stress, which may be a major component of their toxicity. As was the case for their Fe complexes, the toxicity of PIH analogues was enhanced by glutathione depletion of Jurkat cells and eicosapentaenoic acid-loading of K562 cells. Thus the toxicity of the chelators themselves is also enhanced by compromised cellular redox status. In addition, the toxicity of the chelators was diminished by culturing Jurkat cells under hypoxic conditions, which may limit the production of the reactive oxygen species that initiate oxidative stress. A significant part of the toxicity of the chelators may be due to intracellular formation of Fe-chelator complexes, which oxidatively destroy the cell.
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin de la Cote-Ste-Catherine, Montreal, Quebec, Canada H3T 1E2.
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Buss
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Neuzil
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Ponka
D001205:Ascorbic Acid; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000633:toxicity*; D015195:Drug Design; D006801:Humans; D007502:Iron Chelating Agents / Q000633:toxicity; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000633:toxicity*; D019169:Jurkat Cells; D020014:K562 Cells; D007700:Kinetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000633:toxicity*; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D007502:Iron Chelating Agents; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D001205:Ascorbic Acid; D007538:Isoniazid