Intracellular Ca²⁺ and Cytotoxicity

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⁺.