THE INFLUENCE OF ZINC ON APOPTOSIS

This review summarizes the evidence that apoptosis is modulated by int racellular excess or deficiency of Zn2+,considers mechanisms whereby Z n2+ may influence apoptosis, and delineates gaps in current knowledge and opportunities for research. The experimental evidence supports fou r major conclusions: [I] Zinc deficiency, resulting from dietary depri vation of mice, or exposure of cultured cells to membrane-permeable Zn 2+-chelators, can induce apoptosis; [2] Zinc supplementation, either b y pretreating mice with ZnSO4, or adding 4, Zn2+ to the media of cell cultures, can prevent apoptotic death. Zn2+ protects against the apopt osis induced by diverse physical, chemical, or immunologic stimuli in cultured cells of lymphoid, hepatic, or neoplastic origin; [3] Zn2+ do es not affect the triggering events or earliest signs of apoptosis, bu t acts later in the apoptotic pathway,preventing endonucleosomal fragm entation and subsequent cytolysis; and [4] An intracellular pool of ch elatable Zn2+ plays a critical role in apoptosis, possibly by modulati ng the activation or activity of endonuclease(s). These conclusions sh ould alert pharmacologists and physicians to the potential therapeutic applications of zinc compounds and zinc chelators in clinical disorde rs and diseases that involve apoptosis, and to the relevance of zinc n utrition in such conditions.