Augmentation of human and rat lenticular glutathione in vitro by prodrugs of γ-L-glutamyl-L-cysteine

Herbert T. Nagasawa, Jonathan F. Cohen, Ann M. Holleschau, William B. Rathbun

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

A marked age-related decrease in glutathione (GSH) levels as well as depression of γ-glutamyl-cysteine synthetase activity are factors that are believed to render the aged lens more susceptible to oxidative stress and, therefore, to cataractogenesis. Providing γ-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 dipeptide 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 cultured human and rat lenses in vitro using an assay that measured the incorporation of [14C]glycine into lens GSH. Ethyl S-acetyl-γ-L-glutamyl-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 γ-L-glutamyl-L-cysteinate (1a), the des-S-acetyl analog of 2, had been shown (by others) to protect against experimental rodent cataracts. GSH augmentation by 1a was 2% in human lenses and 25% in rat lenses, considerably less than that shown by 2.

Original languageEnglish (US)
Pages (from-to)1676-1681
Number of pages6
JournalJournal of medicinal chemistry
Volume39
Issue number8
DOIs
StatePublished - Apr 12 1996

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