The Final Steps to Toxic Cell Death

Abstract

More than 20 years ago Judah proposed that for a series of hepatotoxins the pathways to cell killing could be subdivided into two parts, one part specific to a given hepatotoxin and the other a final common pathway involving Ca²⁺ influx. With the development of suitable hepatocyte culture systems the proposal was tested. A wide variety of hepatotoxins killed in the presence of extracellular Ca²⁺ but not in its absence. Although these results were interpreted in terms of a final common pathway to cell death analogous to Judah's proposal, it has become clear that the Ca²⁺-mediated final pathway is not universal. Additional study of the biochemical mechanism of Ca²⁺-rnediated cell killing in cultured mouse fibroblasts treated with divalent cation ionophore A23187 plus Ca²⁺ have demonstrated the existence of at least two Ca²⁺-dependent steps and a Na⁺-dependent step, the first Ca²⁺-dependent step being associated with the release of arachidonic acid from cellular phospholipids. These studies have also provided a useful basis for classifying final cell killing mechanisms as either fast or slow mechanisms. Fast mechanisms, which kill cells too rapidly to involve elevated intracellular Ca2⁺, include (i) dissolution of cell membranes, (ii) physical disruption of membranes, (iii) gross denaturation of cellular proteins, and (iv) chemical degradation of vital cell components. Slow mechanisms, which may or may not involve Ca²⁺ as part of the final pathway to cell death, include (i) energy deprivation, (ii) oxidative damage, (iii) radiation damage, (iv) inhibition of macromolecule synthess, and (v) senescence. Further understanding of the final pathways to cell death may lead to the development of effectve drugs to arrest cell killing processes in diseases such as myocardial infarction and stroke.