PREVENTION OF ACETAMINOPHEN-INDUCED AND NAPHTHALENE-INDUCED CATARACT AND GLUTATHIONE LOSS BY CYSSME

Purposes. To assess the efficacy of 2-mercaptoethanol/L-cysteine mixed disulfide (CySSME) as an L-cysteine prodrug suitable for glutathione biosynthesis in rat lenses in vitro, as an agent for the prevention of acetaminophen- and naphthalene-induced murine cataract in genetically -susceptible mice, and as an agent for maintenance of near-normal glut athione levels in lenses and livers of mice subjected to acetaminophen and naphthalene at cataractogenic doses. Methods. Synthetic CySSME wa s added as a prodrug to rat lens culture medium devoid of L-cystine an d L-methionine but containing [C-14(U)]-glycine. After a 48-hour perio d of incubation, extracts of rat lenses were prepared for separation o f [C-14]-glutathione by high-performance liquid chromatography (HPLC) with a radioisotope detector to determine the extent of its biosynthes is. Cytochrome P-450 isozymes were induced in C57 bl/6 mice by either beta-naphthoflavone or phenobarbital. Cataracts were induced by admini stration of either acetaminophen or naphthalene to the pretreated mice . CySSME was coadministered with either acetaminophen or naphthalene t o other groups of mice. Both oxidized and reduced glutathione were det ermined in extracts of livers and lenses using the HPLC method above. Results, CySSME served as an effective L-cysteine precursor for glutat hione biosynthesis in cultured rat lenses. This L-cysteine prodrug was also highly effective in preventing acetaminophen- and naphthalene-in duced cataract in mice and in maintaining near-normal glutathione leve ls in lenses and livers of such treated animals. Conclusions. This inv estigation demonstrates that maintenance of adequate physiological lev els of glutathione in the presence of specific known cataractogenic ag ents by pharmacologic intervention with CySSME, an L-cysteine prodrug, is sufficient to prevent cataract formation.