Prevention of acetaminophen- and naphthalene-induced cataract and glutathione loss by CySSME.
OBJECTIVE
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 glutathione levels in lenses and livers of mice subjected to acetaminophen and naphthalene at cataractogenic doses.


METHODS
Synthetic CySSME was added as a prodrug to rat lens culture medium devoid of L-cystine and L-methionine but containing [14C(U)]-glycine. After a 48-hour period of incubation, extracts of rat lenses were prepared for separation of [14C]-glutathione by high-performance liquid chromatography (HPLC) with a radioisotope detector to determine the extent of its biosynthesis. Cytochrome P-450 isozymes were induced in C57 bl/6 mice by either beta-naphthoflavone or phenobarbital. Cataracts were induced by administration of either acetaminophen or naphthalene to the pretreated mice. CySSME was coadministered with either acetaminophen or naphthalene to other groups of mice. Both oxidized and reduced glutathione were determined in extracts of livers and lenses using the HPLC method above.


RESULTS
CySSME served as an effective L-cysteine precursor for glutathione biosynthesis in cultured rat lenses. This L-Cysteine prodrug was also highly effective in preventing acetaminophen- and naphthalene-induced cataract in mice and in maintaining near-normal glutathione levels in lenses and livers of such treated animals.


CONCLUSIONS
This investigation demonstrates that maintenance of adequate physiological levels of glutathione in the presence of specific known cataractogenic agents by pharmacologic intervention with CySSME, an L-cysteine prodrug, is sufficient to prevent cataract formation.
Rathbun
W B
WB
Department of Ophthalmology, University of Minnesota, Minneapolis, MN 55455, USA.
Holleschau
A M
AM
Cohen
J F
JF
Nagasawa
H T
HT
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D002386:Cataract / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000494:pharmacology / Q000627:therapeutic use*; D004338:Drug Combinations; D005978:Glutathione / Q000378:metabolism*; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008623:Mercaptoethanol / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000633:toxicity*; D009924:Organ Culture Techniques; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms
D018712:Analgesics, Non-Narcotic; D004338:Drug Combinations; D009281:Naphthalenes; D011355:Prodrugs; C031721:naphthalene; D000082:Acetaminophen; D008623:Mercaptoethanol; D005978:Glutathione; D003545:Cysteine