N-linked glycoside and glucuronide conjugates of the retinoid, acitretin, are biologically active in cornea and conjunctiva

The purpose of this study was to test two water-soluble, synthetic retinoids, glucoseamido acitretin and glucuronamido acitretin, for biological activity in cells of the cornea and conjunctiva. Vitamin A-deficient, xerophthalmic rats were treated topically with these retinoids, and corneas were examined histologically for effects on epithelial keratinization. The effect of these retinoids on the proliferation of rabbit conjunctival fibroblasts in culture was also investigated. Glucoseamido acitretin treatment restored a normal cornea after eight to nine days of treatment, while no improvement was observed in the vehicle-treated corneas. Likewise, glucuronamido acitretin application restored a normal corneal surface and reversed keratinization after eight to ten days of treatment. These retinoids caused no irritation of the eye or ocular adnexa. In culture, exposure of conjunctival fibroblasts to glucoseamide acitretin inhibited cell proliferation. Cultures exposed to glucoseamido acitretin at 10(-8) M or 10(-6) M had cell densities 77.3% and 51.9% of control, respectively, after seven days. Glucuronamido acitretin also inhibited cell proliferation. Cultures exposed to glucuronamido acitretin at 10(-8) M had a cell density of 69.2% of control at day seven, while at 10(-6) M this retinoid completely inhibited cell proliferation. These results show that glucoseamide acitretin and glucuronamido acitretin are biologically active in the cornea and conjunctiva, and may be considered for ophthalmic use in diseases involving abnormalities of ocular surface cell differentiation or hyperproliferation of fibroblasts.