The final steps to toxic cell death

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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.

Original languageEnglish (US)
Pages (from-to)191-249
Number of pages59
JournalToxin Reviews
Volume4
Issue number2
DOIs
StatePublished - 1985

Bibliographical note

Funding Information:
was supported by National Science Foundation grant PCM 80-11784

Funding Information:
and National Institutes of Health grant GM 33479.

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