The Role of Glutathione in the Toxicity of Xenobiotic Compounds: Metabolic Activation of 1,2-Dibromoethane by Glutathione

Abstract

Glutathione (GSH) is a ubiquitous tripeptide involved in cellular defense mechanisms and the metabolism of xenobiotic compounds. Detoxification of free radicals and activated oxygen species by direct reaction, as well as that mediated by the enzymic activity of glutathione peroxidase, is a well known and described biochemical function.Equally well known and described is the role of GSH in conjugation. Conjugation with GSH occurs nonenzymatically and through the action of GSH S-transferases. Leukotrienes, active autacoids thought to be involved in inflammatory processes, are formed by the conjugation of GSH with fatty acids derived from arachidonic acid. One important function of GSH S-transferases is the conjugation of GSH with certain xenobiotic compounds, thus enhancing excretion of the xenobiotic. Furthermore, activated metabolites produced from xenobiotic compounds by the action of mixed function oxygenase may also be conjugated with GSH. This occurs both directly and enzymatically. The net result of conjugation with active metabolites is detoxification of these reactive chemical species. In certain cases, the GSH conjugate may ultimately result in toxic reactions. Stepwise, enzymatic degradation of certain GSH conjugates may result in reactive intermediates that result in tissue injury. Some glutathione conjugates, for example, may be enzymatically toxified by the sequential actions of gamma-glutamyl transferase and cysteine conjugate beta-lyase (Dohn and Anders, 1982). Other GSH conjugates may undergo intramolecular rearrangement to unstable intermediates that also result in toxic reactions. For example, the conjugation of vicinaldihaloalkanes may result in an intramolecular rearrangement to a reactive, transitory episulfonium ion (van Bladeren et al., 1980; Schasteen and Reed, 1981; Livesay and Anders, 1982).