Intracellular Ca2+and Cytotoxicity

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Abstract
Following injury or activation in some immune cell lines, elevation of intracellular Ca2+ concentration (Ca i 2+) is an early and major event that precedes cell death. Agents shown to elevate Ca i 2+ and to result subsequently in the death of some cells include human immunodeficiency virus (HIV) (in T4 + cells), 25-hydroxy cholesterol, tumor necrosis factor (TNF), cyclosporine, dexamethasone, α-interferon, and Ca2+ ionophores. The effects of these agents, both on Ca i 2+ and on cytotoxicity, are additive. This type of Ca2+-related cytotoxicity may be associated with either accelerated synthesis of triglycerides (TNF), accelerated synthesis of cholesterol ester (25-hydroxy cholesterol), or cholesterol (HIV) and terminally with declining synthesis of structural phospholipid. Agents that can lower Ca i 2+ (e.g., phorbol esters, diglycerides, lipoproteins [LDL], oleic acid, or serum) under appropriate conditions ameliorate the Ca2+-induced cytotoxicity.1,2 Metabolism of other divalent metals, i.e., Zn2+ and Cd2+, also become altered with cell injury, e.g., glucocorticoids elevate Ca i 2+, but block uptake of Zn2+. These observations support the idea that chronic elevation of Ca i 2+ by many chemically unrelated agents leads to cell death by creating imbalance both in cell biosynthetic mechanisms—especially in those controlling lipid metabolism—as well as creating imbalances in metabolism of other trace metals, especially Zn2+.