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 Fechelator 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 acidloading 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.
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Conference Article|
August 01 2002
The role of oxidative stress in the toxicity of pyridoxal isonicotinoyl hydrazone (PIH) analogues
J. L. Buss;
J. L. Buss
1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin de la Cote-Ste-Catherine, Montreal, Quebec, Canada H3T IE2
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J. Neuzil;
J. Neuzil
1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin de la Cote-Ste-Catherine, Montreal, Quebec, Canada H3T IE2
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P. Ponka
P. Ponka
1
1Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin de la Cote-Ste-Catherine, Montreal, Quebec, Canada H3T IE2
1To whom correspondence should be addressed (e-mail prem.ponka@mcgill.ca)
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Publisher: Portland Press Ltd
Received:
March 10 2002
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (4): 755–758.
Article history
Received:
March 10 2002
Citation
J. L. Buss, J. Neuzil, P. Ponka; The role of oxidative stress in the toxicity of pyridoxal isonicotinoyl hydrazone (PIH) analogues. Biochem Soc Trans 1 August 2002; 30 (4): 755–758. doi: https://doi.org/10.1042/bst0300755
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