NOVEL METABOLIC PATHWAYS OF GLUTATHIONE CONJUGATES AND THEIR RELATION TO TOXICITY

Glutathione conjugation and subsequent mercapturic acid formation have long been considered as one of the major pathway of detoxication. In recent years, however, glutathione or its related conjugates of some halogenated alkanes and alkenes have been found to serve as bioactive nephrotoxicants. On the basis of the activation mechanism, those nephrotoxic sulfur-containing conjugates can be classified into three types: 1) direct-acting conjugates, 2) canjugates requiring metabolic activation, 3) others. Direct-acting toxins including S-(1,2-dihaloethyl) glutathiones are strong alkylating agents. The β-halogen atom is displaced with a sulfur atom to result in the formation of highly reactive episulfoniumion, which is likely to react with the nucleophilic sites of bio-macromolecules. The second class of nephrotoxicants that require metabolic activation to express toxicity includes sulfur-containing conjugates of halogenated alkenes. In the diverse metabolic pathways, some metabolites such as sulfenic acids, thioacetaldehydes, and thiols are probably associated with the expression of toxicity. Among them, participation of the unstable thiols has been extensively studied. It is postulated that the penultimate intermediate thiols give rise to halothionoacyl halides and halothioketenes. Further studies on the whole metabolic pathway of sulfur containing conjugates as well as their toxicity will give light on how each pathway contributes to toxicity. © 1990, The Pharmaceutical Society of Japan. All rights reserved.