Trapping of metabolically generated electrophilic species with cyanide ion: metabolism of 1-benzylpyrrolidine

Abstract

The toxicity of a variety of lipophilic xenobiotics is thought to involve oxidative metabolism of the parent compound to reactive electrophiles which alkylate nucelophilic functionalities present on macromolecules. Incubations of 1-benzylpyrrolidine (4) and specifically deuterium-labeled analogues of 4 with rabbit liver microsomal preparations in the presence of cyanide ion have led to the characterization of 1-benzyl-2-cyanopyrrolidine, cis- and trans-1-benzyl-2,5-dicyanopyrrolidine, and 1-benzyl-5-cyano-2-pyrrolidinone. The cyano adducts of the amine are thought to result from nucleophilic attack by cyanide ion on metabolically generated iminium species. The cyanolactam may be produced by mixed function oxidation of the dicyano compounds. Incubation of 3H-labeled 1-benzylpyrrolidine with rabbit liver microsomal preparations led to the reduced NADP dependent incorporation of the label into the macromolecular fraction isolated from the postincubates. Although the level of incorporation was low compared to the amount of cyano adducts formed, it is comparable to that reported for other metabolically activated cytotoxic agents. Attempts to identify the possible arene oxide rearrangement product 1-(4-hydroxybenzyl)pyrrolidine as a metabolite of 4 of alkylating nucleophilic functionalities present on microsomal macromolecules.