M. Jung et al., Effects of hepatocellular iron imbalance on nitric oxide and reactive oxygen intermediates production in a model of sepsis, J HEPATOL, 33(3), 2000, pp. 387-394
Background/Aims: In mammals iron homeostasis is most important, as imbalanc
e of iron such as iron overload may lead to severe diseases, Recently, it h
as been shown that the iron regulatory protein-1 is partially controlled by
nitric oxide and reactive oxygen intermediates, molecules frequently seen
in inflammatory events. The aim of the present study was to investigate the
effects of impaired iron homeostasis on the interaction of nitric oxide, a
nd reactive oxygen intermediate formation in hepatocytes in a model of acut
e inflammation.
Methods: Hepatocytes isolated from Corynebactericum parvum (C. parvum)-inje
cted rats were used to examine the formation of nitrogen and oxygen interme
diates by iron deprivation and iron overload in the presence of lipopolysac
charide. In addition, we investigated the RNA binding and aconitase activit
y of iron regulatory protein-1.
Results: In the present study we show that iron overload in lipopolysacchar
ide-treated C. parvum-primed hepatocytes downregulated the RNA binding of i
ron regulatory protein-1 and aconitase activity. Subsequently, we observed
a reduced formation of nitrite/nitrate and S-nitrosothiols but an increased
production of reactive oxygen species, and hepatocellular damage. Moreover
, the addition of iron to cell cultures caused a further increase in cellul
ar damage, a drop in the cellular glutathione pool, and an increase in pero
xynitrite and hydroxyl-like radicals. In contrast, addition of deferoxamine
(an iron chelator) to lipopolysaccharide-treated C. parvum-primed hepatocy
tes protected cells by stabilizing the GSH content, maintaining the nitric
oxide formation, and by reducing Fenton oxidants,
Conclusions: Our results show that the antioxidative effects of iron chelat
ors prevent the formation of toxic Fenton oxidants in severe inflammatory e
vents, which should be considered in the treatment of disorders characteriz
ed by an iron imbalance.