The possible mechanism of naphthalene cataract in rat and its prevention by an aldose reductase inhibitor (ALO1576).
The naphthalene-induced cataract in rats has been studied for many years as a possible model of human aging-related cataract. While the molecular mechanism of this cataract is unclear, it has recently been demonstrated that the aldose reductase inhibitor ALO1576 can prevent lens opacification in this system. The present study was undertaken to investigate the molecular basis for the effects of naphthalene on the lens and the role of pigmentation in the cataractogenic mechanism. Cataracts were induced in five strains of rats (two pigmented, three albino) by oral administration of naphthalene. Initial lens changes were observed after 1 week by slit-lamp; by 3 weeks a distinct shell-like opacity was present in the deep cortex. Little difference in the course of opacification was found between the pigmented and albino strains. Major biochemical effects were a decrease of 20-30% in glutathione (GSH) by 1 week of feeding, disulfide cross-linking of lens proteins present by 3 weeks, and a nearly 20-fold increase in the content of protein-GSH mixed disulfide. No effect was seen in the ability of the affected lenses to accumulate activity [3H]choline or 86Rb from the medium in organ culture nor in the activity of the Na+/K(+)-ATPase. ALO1576 (10 mg kg-1 day-1) completely prevented all morphological and biochemical changes in the lenses of the naphthalene-fed rats in both pigmented and non-pigmented strains. These results indicate that pigmentation is not required for induction of naphthalene cataract in rats. Naphthalene dihydrodiol was found in the aqueous humor and lens of naphthalene-fed rats. It is proposed that naphthalene dihydrodiol produced in the liver reaches the aqueous humor and penetrates the lens where it is further metabolized ultimately to form the toxic species, naphthoquinone.
Xu
G T
GT
Cataract Research, Alcon Laboratories Inc., Fort Worth, TX 76115.
Zigler
J S
JS
Lou
M F
MF
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002386:Cataract / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D003459:Crystallins / Q000378:metabolism; D005449:Fluorenes / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D006827:Hydantoins / Q000627:therapeutic use*; D007908:Lens, Crystalline / Q000378:metabolism / Q000473:pathology; D008297:Male; D009281:Naphthalenes / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D003459:Crystallins; D005449:Fluorenes; D006827:Hydantoins; D009281:Naphthalenes; C052241:imirestat; C031721:naphthalene; D000449:Aldehyde Reductase; D005978:Glutathione