AUGMENTATION OF HUMAN AND RAT LENTICULAR GLUTATHIONE IN-VITRO BY PRODRUGS OF GAMMA-L-GLUTAMYL-L-CYSTEINE

A marked age-related decrease in glutathione (GSH) levels as well as d epression of gamma-glutamylcysteine synthetase activity are factors th at are believed to render the aged lens more susceptible to oxidative stress and, therefore, to cataractogenesis. Providing gamma-L-glutamyl -L-cysteine, the dipeptide precursor of GSH, would effectively bypass the compromised first step in its biosynthesis and should protect the lens from GSH depletion. Accordingly, some bioreversible sulfhydryl-, amino-, and C-terminal carboxyl-protected prodrug forms of this dipept ide were prepared. Sulfhydryl protection was in the form of an acetyl thioester, while the carboxyl group was protected as the ethyl ester. These prodrugs were evaluated for their GSH-enhancing activity in cult ured human and rat lenses in vitro using an assay that measured the in corporation of [C-14]glycine into lens GSH. Ethyl S-acetyl-gamma-L-glu tamyl-L-cysteinate (2) raised GSH levels in human lenses by 25% and in rat lenses by >150%. These data suggest that 2 may have potential as an anticataract agent since ethyl gamma-L-glutamyl-L-cysteinate (1a), the des-S-acetyl analog of 2, had been shown (by others) to protect ag ainst experimental rodent cataracts. GSH augmentation by 1a was 2% in human lenses and 25% in rat lenses, considerably less than that shown by 2.