The Mechanism And Prevention Of Naphthalene Cataract In Rats

The mechanism of naphthalene-induced cataract in rats and the preventive action of AL01576 (an aldose reductase inhibitor, ARI) were studied in both in vivo and in vitro systems. In the in vivo studies, cataracts were induced in 5 strains of rats (2 pigmented, 3 albino) by naphthalene feeding (1.0 g/kg/day). The cataractous changes occured in one week as watercleft and spoke-like opacities which merged to form a shell-like opacity in the deep cortex by 3 weeks. Semi-quantitation of the lens opacities with an arbitary six-score grading system showed little difference in the cataract development between the albino and pigmented strains. Major biochemical changes observed were a decrease of 20%-30% in GSH by one week of feeding, the appearance of disulfide cross-linking of lens proteins by 3 weeks, and a more than ten fold increase in the content of protein-GSH mixed disulfide. Neither damage to lens membrane functions as measured by ³H-choline and ⁸⁶Rubidium uptake or loss of Na⁺/K⁺-ATPase activity was detected. AL01576 (10 mg/kg/day) completely prevented the naphthalene-induced lens changes in both albino and pigmented rats. These results indicate that pigmentation is not necessary for the induction of naphthalene cataract in rat and suggest that tyrosinase action on naphthalene metabolites (such as 1- or 2-naphthol) is not involved in this cataract formation. The in vitro "naphthalene cataract" was established by exposing rat lens to each of five potential naphthalene metabolites in the organ culture system (in modified TC-199 medium) for 48 hrs. When naphthalene dihydrodiol was used, both the morphological and biochemical changes in the lens were very similar to those observed in lens of naphthalene-fed rat, and AL01576 completely blocked these in vitro changes as it did in vivo. Other naphthalene metabolites (1,2-dihydroxy-naphthalene, 1-naphthol, 2-naphthol and 1,2-naphthoquinone) caused changes which were different from those induced by naphthalene in vivo and none of them was prevented by AL01576. These results suggest that naphthalene 1,2-dihydrodiol is the key naphthalene metabolite which reaches the lens via blood and aqueous humor and induces cataract formation when it is metabolized to 1,2-naphthoquinone. This mechanism is further supported by the detection of naphthalene dihydrodiol in the lens and aqueous humor of naphthalene-fed rats by HPLC.Examples of various classes of ARI (AL01576, AL04114, Sorbinil and Tolrestat) were compared for their effects on the formation of naphthalene cataract and a dual cataract induced with simultaneous feeding of galactose and naphthalene. Both AL01576 and AL04114 (spirohy-dantoin derivatives) completely prevented the changes in the lenses of naphthalene-fed rats. However, Sorbinil (another spirohydantoin ARI) demonstrated a much weaker efficacy in this model and the carboxylic acid ARI, Tolrestat, showed no efficacy at all. In the dual cataract, Tolrestat prevented the lenticular changes induced by galactose and reduced the dulcitol accu-...