REDOX-CYCLING OF IRON IONS TRIGGERS CALCIUM-RELEASE FROM LIVER-MICROSOMES

Elevation of cytosolic calcium levels has been shown to occur via oxid ation of critical protein thiols in liver microsomes. Elevated cytosol ic Ca2+ may also result from activation of calcium releasing channels. In the presence of NADPH or ascorbic acid, iron ions produced a conce ntration-dependent release of calcium from liver microsomes. Under ana erobic conditions, the iron-induced release of calcium was inhibited, suggesting that a reaction of oxidation triggers the releasing process . The calcium releasing process at pH 7.0 appears to be highly sensiti ve to activation by iron ions, as effective concentrations (e.g., 2-5 mu M) did not alter the Ca2+, Mg2+-ATPase or the phospholipid componen t of the microsomal membranes. Iron-induced Ca2+-release could occur u nder conditions in which there was no iron-induced microsomal lipid pe roxidation. Under conditions of intense lipid peroxidation, PEN fully prevented the iron-induced accumulation of thiobarbituric reactive rea gents without affecting the release of Ca2+, suggesting that lipid per oxidation is not the mechanism by which iron causes release of calcium . Trolox, GSH and high concentrations of ascorbate, however, strongly inhibited the iron-induced calcium release, most likely due to modulat ion of the Fe2+/Fe3+ ratio. While the IP3 receptor system is considere d to be the main regulator of calcium release, Liver also contains a r yanodine-sensitive calcium releasing store. The iron-induced calcium r elease at pH 7.0 was blocked by ruthenium red, a specific inhibitor of the ryanodine receptor, and Fe2+ (but not Fe3+) decreased the binding of ryanodine, a specific ligand for the ryanodine-sensitive calcium c hannel. These results suggest that redox-cycling of iron ions results in an activation of a ryanodine-sensitive calcium channel. Activation of calcium releasing channels by iron may play a role in the evolution of various hepatic disorders that are associated with chronic iron ov erload in humans. (C) 1998 Elsevier Science Inc.