Abstract
Glutathione conjugation, which has long been considered as a major detoxication pathway, leads to the formation of toxic metabolites in certain kinds of xenobiotics. Sulfur-containing conjugates are classified into three types on the basis of mechanism of toxication : Type I ) conjugates that exert toxicity without bioactivation (direct-acting conjugates), Type II) conjugates that require metabolic activation, and Type III) conjugates that are transported to the target cell and exert their toxicity upon deconjugation. This review summarizes the current knowledge on the vast metabolic pathway of cysteine conjugates and the mechanism of toxication of the conjugates classified into the type II. Metabolic pathway of cysteine conjugates includes : 1) N-acetylation, 2) C-S cleavage, 3) deamination, 4) S-oxidation, and 5) decarboxylation. Among these, the involvement of C-S cleavage pathway in the toxication of cysteine conjugates is well established. Cysteine conjugates of some halogenated alkenes that are categorized to the type II are converted to chemically reactive thiols by the action of cysteine conjugate β-lyase. The penultimate toxic intermediates, thiols, are further converted to highly electrophilic thionoacyl halides or thioketenes which covalently bind to nucleophilic site of cellular macromolecules. In addition, we discuss possible contribution of other metabolic pathways to the toxication of cysteine conjugates.
