The Influence of Zinc on Apoptosis*f

This review summarizes the evidence that apoptosis is m odulated by intracellular excess or deficiency of Zn2 + , considers mechanisms whereby Zn2+ may influence apoptosis, and delineates gaps in current knowledge and opportunities for research. The experimental evidence supports four major conclusions: [1] Z inc deficiency, resu lting from dietary deprivation of m ice, or exposure of cultured cells to m em brane-perm eable Zn 2 +-chelators, can induce apoptosis; [2] Zinc supplementation, either by pretreating mice with Z nS 04, or adding Zn2+ to the media of cell cultures, can prevent apoptotic death. Zn2+ protects against the apoptosis induced by diverse physical, chemical, or imm uno­ logic stimuli in cultured cells of lymphoid, hepatic, or neoplastic origin; [3] Zn2+ does not affect the triggering events or earliest signs of apo­ ptosis, but acts later in the apoptotic pathway, preventing endonucleosomal fragmentation and subsequent cytolysis; and [4] An intracellular pool of chelatable Zn2+ plays a critical role in apo­ ptosis, possibly by m odulating the activation or activity of endonuclease(s). These conclusions should alert pharmacologists and physicians to the potential therapeutic applications of zinc compounds and zinc chelators in clinical disorders and diseases that involve apoptosis, and to the relevance of zinc nutrition in such conditions.