Failure of glutathione and cysteine prodrugs to block the chlorpropamide-induced inhibition of aldehyde dehydrogenase in vivo.
Augmentation of cellular L-cysteine or glutathione (GSH) levels in vivo by the administration of prodrugs of L-cysteine or GSH, viz. 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (MTCA), 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-car boxylic acid (RibCys) and GSH monoethyl ester (GSH-OEt), did not block the inhibition of aldehyde dehydrogenase (AlDH) by chlorpropamide (CP) or N1-ethylchlorpropamide (N1-EtCP), as shown by their inability to protect AlDH and thereby prevent the elevation of blood acetaldehyde (AcH) in ethanol-treated rats. Since the formation of an alkylcarbamoylating species by conjugation of n-propylisocyanate, a potential metabolite of CP or N1-EtCP, with GSH or L-cysteine is possible, intervention by GSH or cysteine may not produce a detoxified product. Evaluation of the two products that could theoretically be produced in vivo, viz. S-(n-propylcarbamoyl)-L-cysteine and S-(n-propylcarbamoyl)-GSH, indicated that these compounds inhibit rather than spare AlDH in rats. Indeed, the latter were as effective as N1-EtCP, a direct acting inhibitor of AlDH, and all three were better inhibitors of AlDH in vivo than CP itself. Thus, formation of S-conjugates of the active CP metabolite produced in vivo may not be a detoxication process, but may in fact represent redistribution of a transportable form of this highly reactive metabolite.