Oxidative stress mediates toxicity of pyridoxal isonicotinoyl hydrazone analogs.
Pyridoxal isonicotinoyl hydrazone (PIH) and many of its analogs are effective iron chelators in vivo and in vitro, and are of interest for the treatment of secondary iron overload. Because previous work has implicated the Fe(3+)-chelator complexes as a determinant of toxicity, the role of iron-based oxidative stress in the toxicity of PIH analogs was assessed. The Fe(3+) complexes of PIH analogs were reduced by K562 cells and the physiological reductant, ascorbate. Depletion of the antioxidant, glutathione, sensitized Jurkat T lymphocytes to the toxicity of PIH analogs and their Fe(3+) complexes, and toxicity of the chelators increased with oxygen tension. Fe(3+) complexes of pyridoxal benzoyl hydrazone (PBH) and salicyloyl isonicotinoyl hydrazone (SIH) caused lipid peroxidation and toxicity in K562 cells loaded with eicosapentenoic acid (EPA), a readily oxidized fatty acid, whereas Fe(PIH)(2) did not. The lipophilic antioxidant, vitamin E, completely prevented both the toxicity and lipid peroxidation caused by Fe(PBH)(2) in EPA-loaded cells, indicating a causal relationship between oxidative stress and toxicity. PBH also caused concomitant lipid peroxidation and toxicity in EPA-loaded cells, both of which were reversed as its concentration increased. In contrast, PIH was inactive, while SIH was equally toxic toward control and EPA-loaded cells, without causing lipid peroxidation, indicating a much smaller contribution of oxidative stress to the mechanism of toxicity of these analogs. In summary, PIH analogs and their Fe(3+) complexes are redox active in the intracellular environment. The contribution of oxidative stress to the overall mechanism of toxicity varies across the series.
Buss
Joan L
JL
Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC, USA.
Neuzil
Jiri
J
Ponka
Prem
P
D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000737:chemistry / Q000633:toxicity; D005297:Ferrozine / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007502:Iron Chelating Agents / Q000737:chemistry / Q000633:toxicity*; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D019169:Jurkat Cells; D020014:K562 Cells; D015227:Lipid Peroxidation / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000633:toxicity; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*
D001095:Arachidonic Acids; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D005297:Ferrozine; D011730:Pyridoxal; D019328:Buthionine Sulfoximine; C021079:pyridoxal isonicotinoyl hydrazone; D005978:Glutathione; D010100:Oxygen; D007538:Isoniazid