The biochemical pathology of toxic cell death.

The toxicity of chemicals is, in most cases, a consequence of their metabolism, and the cytochrome P450-dependent mixed function oxidases are the most common mechanisms mediating such biotransformations. The mechanisms linking metabolism to the genesis of lethal cell injury is a central concern of biochemical pathology. For many years it has been widely held that cellular injury is mediated by the interaction of chemically reactive metabolites with macromolecules. The evidence to support such an hypothesis is largely circumstantial. There is, however, little or no data relative to the nature of the cellular targets of covalent binding or the functional consequences that result from the interactions between the chemical toxin and key cellular macromolecules. Recent studies have provided alternative mechanisms. Emphasis has been given to recently described changes in intracellular calcium homeostasis, changes in thiol status, and the role of acute oxidative stress imposed by the formation of activated oxygen species. Future studies can be expected to focus on the nature and extent of the membrane injury mediated by such oxygen metabolites and on the relationship between such membrane damage and alterations in calcium and thiol homeostasis.