The role of glutathione in the toxicity of xenobiotic compounds: metabolic activation of 1,2-dibromoethane by glutathione.

Unstable metabolites may arise during the metabolism of xenobiotic compounds with enzyme systems other than the cytochrome P-450 system. This depends on the enzyme system involved and the structure of the xenobiotic compound being metabolized. Normally detoxifying pathways may transform selected chemicals into toxic metabolites. In our laboratory we have demonstrated that DBE is metabolized by both cytochrome P-450 and GSH S-transferases. Although the cytochrome P-450 metabolite is reactive and will covalently bind to protein and nucleic acid to some extent, and the GSH S-transferase system conjugates it and under conditions of low DBE exposure is able to detoxify it. In contrast, GSH S-transferase catalyzes the direct conjugation of GSH with DBE. This can result in formation of a reactive intermediate that preferentially binds to nucleic acids and is responsible for the DNA damage observed following DBE exposure. The selective toxicity of this xenobiotic compound may be due to the preponderance of activating GSH conjugating enzymes in the extrahepatic organs. However, this difference alone does not appear sufficient to explain the selection of extrahepatic organs as sites of DBE-induced toxicity.