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The Iron Chelator L1 Potentiates Oxidative DNA Damage in
Iron-Loaded Liver Cells
Louise Cragg,
Robert P. Hebbel,
Wesley Miller,
Alex Solovey,
Scott Selby, and
Helen Enright
From the Department of Medicine-Hematology, University of Minnesota
Medical School, Minneapolis, MN.
Iron-mediated carcinogenesis is thought to occur through the
generation of oxygen radicals. Iron chelators are used in attempts to
prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron
overload, we studied the generation of iron-catalyzed oxidative DNA
damage and the influence of iron chelators, including L1, on such
damage. Iron loading of HepG2 cells was found to greatly exacerbate
hydrogen peroxide-mediated DNA damage. Desferrithiocin was protective
against iron/hydrogen peroxide-induced DNA damage; deferoxamine had no
effect. In contrast, L1 exposure markedly potentiated hydrogen
peroxide-mediated oxidative DNA damage in iron-loaded liver cells.
However, when exposure to L1 was maintained during incubation with
hydrogen peroxide, L1 exerted a protective effect. We interpret this as
indicating that L1's potential toxicity is highly dependent on the
L1:iron ratio. In vitro studies examining iron-mediated ascorbate
oxidation in the presence of L1 showed that an L1:iron ratio must be at
least 3 to 1 for L1 to inhibit the generation of free radicals; at
lower concentrations of L1 increased oxygen radical generation occurs.
In the clinical setting, such potentiation of iron-catalyzed oxidative
DNA damage at low L1:iron ratios may lead to long-term toxicities that
might preclude administration of L1 as an iron chelator. Whether this
implication in fact extends to the in vivo situation will have to be
verified in animal studies.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 632-638
© 1998 by the American Society of Hematology.
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