title: Redox-cycling of iron ions triggers calcium release from liver microsomes.
abstract: Elevation of cytosolic calcium levels has been shown to occur via oxidation of critical protein thiols in liver microsomes. Elevated cytosolic Ca2+ may also result from activation of calcium releasing channels. In the presence of NADPH or ascorbic acid, iron ions produced a concentration-dependent release of calcium from liver microsomes. Under anaerobic 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 sensitive to activation by iron ions, as effective concentrations (e.g., 2-5 microM) did not alter the Ca2+, Mg2+-ATPase or the phospholipid component of the microsomal membranes. Iron-induced Ca2+-release could occur under conditions in which there was no iron-induced microsomal lipid peroxidation. Under conditions of intense lipid peroxidation, PBN fully prevented the iron-induced accumulation of thiobarbituric reactive reagents without affecting the release of Ca2+, suggesting that lipid peroxidation 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 modulation of the Fe2+/Fe3+ ratio. While the IP3 receptor system is considered to be the main regulator of calcium release, liver also contains a ryanodine-sensitive calcium releasing store. The iron-induced calcium release 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 channel. 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 overload in humans.
authors.affiliation: Department of Biochemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Stoyanovsky
authors.forename: A I
authors.initials: AI
authors.lastname: Cederbaum
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D017301:Ca(2+) Mg(2+)-ATPase / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D005609:Free Radicals; D007501:Iron / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009249:NADP / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000378:metabolism*
chemical_list: D005609:Free Radicals; D012433:Ryanodine; D009249:NADP; D007501:Iron; D017301:Ca(2+) Mg(2+)-ATPase; D001205:Ascorbic Acid; D002118:Calcium