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Hypothermia injury/cold-induced apoptosis—evidence of an increase in chelatable iron causing oxidative injury in spite of low O₂^-/H₂O₂ formation

Institut für Physiologische Chemie, Universitätsklinikum, D-45122 Essen, Germany

¹Correspondence: Institut für Physiologische Chemie, Universitätsklinikum, Hufelandstr. 55, D-45122 Essen, Germany. E-mail: ursula.rauen{at}uni-essen.de

When incubated at 4°C, cultured rat hepatocytes or liver endothelial cells exhibit pronounced injury and, during earlier rewarming, marked apoptosis. Both processes are mediated by reactive oxygen species, and marked protective effects of iron chelators as well as the protection provided by various other antioxidants suggest that hydroxyl radicals, formed by classical Fenton chemistry, are involved. However, when we measured the Fenton chemistry educt hydrogen peroxide and its precursor, the superoxide anion radical, formation of both had markedly decreased and steady-state levels of hydrogen peroxide did not alter during cold incubation of either liver endothelial cells or hepatocytes. Similarly, there was no evidence of an increase in O₂^-/H₂O₂ release contributing to cold-induced apoptosis occurring on rewarming. In contrast to the release/level of O₂^- and H₂O₂, cellular homeostasis of the transition metal iron is likely to play a key role during cold incubation of cultured hepatocytes: the hepatocellular pool of chelatable iron, measured on a single-cell level using laser scanning microscopy and the fluorescent indicator phen green, increased from 3.1 ± 2.3 µM (before cold incubation) to 7.7 ± 2.4 µM within 90 min after initiation of cold incubation. This increase in the cellular chelatable iron pool was reversible on rewarming after short periods of cold incubation. The cold-induced increase in the hepatocellular chelatable iron pool was confirmed using the calcein method. These data suggest that free radical-mediated hypothermia injury/cold-induced apoptosis is primarily evoked by alterations in the cellular iron homeostasis/a rapid increase in the cellular chelatable iron pool and not by increased formation of O₂^-/H₂O₂.—Rauen, U., Petrat, F., Li, T., de Groot, H. Hypothermia injury/cold-induced apoptosis—evidence of an increase in chelatable iron causing oxidative injury in spite of low O₂^-/H₂O₂ formation.

Key Words: hydrogen peroxide • superoxide anion radical • hydroxyl radical • Fenton reaction • transition metal ions

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