3 - Calcium and signal transduction in oxidative cell damage

Summary

Introduction

In aerobically growing eukaryotic cells, ATP synthesis is coupled to the enzymatic reduction of molecular oxygen (O₂) to H₂O via a sequential, four-electron transfer reaction. However, one- and two-electron reduction of O₂ can also occur under physiological conditions in mitochondria and other cellular compartments, generating superoxide anion free radicals (O₂⁻) and other active oxygen species, including hydrogen peroxide (H₂O₂) and the hydroxyl radical (OH) (Fridovich, 1983). Although several intracellular mechanisms exist that normally prevent the accumulation of active oxygen species during cell metabolism, these protective systems can become overwhelmed and toxic damage to cells may follow. Thus, accumulating evidence implicates oxygen radicals and other oxygen-derived species as causative agents in ageing and a variety of human diseases, including cancer (Cerutti, 1985).

The term ‘oxidative stress’ is generally applied to conditions in which the intracellular prooxidant–antioxidant ratio favours the former (Sies, 1985). Recent studies by our laboratory and others have examined the effects of oxidative stress on various cellular functions. Experimental systems commonly used to expose various types of cells and tissues to oxidative stress include enzymatic generation of active oxygen species (e.g. using xanthine/xanthine oxidase) (Muehlematter, Larsson & Cerutti, 1988), direct exposure to peroxides or prooxidants (Sies, Brigelius & Graf, 1987) and intracellular generation of active oxygen species by treatment with redox-cycling chemicals such as quinones or bipyridilium compounds (Smith et al., 1985; Orrenius et al., 1986).