PREVENTION OF NAPHTHALENE-INDUCED CATARACT AND HEPATIC GLUTATHIONE LOSS BY THE L-CYSTEINE PRODRUGS, MTCA AND PTCA

Rapid-onset cataracts were induced in SPF C57 bl/6 mice by intraperito neal administration of naphthalene following cytochrome P-450 isozyme induction with phenobarbital. Several L-cysteine prodrugs with masked sulfhydryl groups in the form of thiazolidine-4-carboxylic acids, as w ell as N-acetyl-L-cysteine, N,S-bis-acetyl-L-cysteine and glutathione ethyl ester, were evaluated for their ability to maintain hepatic and lenticular glutathione at near-normal levels and to prevent naphthalen e-induced cataract formation. Each prodrug was administered at three s pecified times to a cumulative total of 1.5 mole equivalents of the si ngle dose of naphthalene. Three L-cysteine prodrugs delayed but did no t prevent cataract formation in 40-60% of the mice over a 72-hr period , while eight of the 13 compounds produced cataract yields similar to the naphthalene control animals, i.e. 83% in 72 hr, However, two L-cys teine prodrugs, 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (MTCA) and 2(R,S)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA), prevented cataract formation in 20 of 21 and 12 of 12 mice, respectively, and m aintained hepatic reduced glutathione levels at 82% and 51% of untreat ed controls, In contrast, glutathione was depressed to 3% of the norma l value in those animals treated with naphthalene alone. Lenticular gl utathione values were depressed, albeit minimally, in all naphthalene- treated mice regardless of administration of either MTCA or PTCA. The mice protected with either MTCA or PTCA showed no visible effects of n aphthalene toxicity or lens opacities at any time, It can be concluded that these L-cysteine prodrugs were effective in preventing naphthale ne-induced cataract and maintaining near-normal hepatic glutathione le vels. (C) 1996 Academic Press Limited