STEROID-INDUCED CATARACT - NEW PERSPECTIVES FROM IN-VITRO AND LENS CULTURE STUDIES

The prevailing view regarding the mechanism of steroid cataract format ion holds that glucocorticoids are covalently bound to lens proteins r esulting in destabilization of the protein structure allowing further modification (i.e. oxidation) leading to cataract. Alternative hypothe ses (e.g. that cataracts result from glucocorticoid receptor mediated effects) have been difficult to test since protein binding does in fac t occur for many cataractogenic steroids. A glucocorticoid lacking the typical glucocorticoid hydroxy group at C21 (fluorometholone, FML), o ther steroids which can bind to proteins but lack glucocorticoid activ ity, and a glucocorticoid antagonist (RU486) have been utilized to dis criminate between these two hypotheses. Purified bovine beta-crystalli n incubated with three different H-3-steroids, dexamethasone (Dex), al dosterone or progesterone demonstrated that the C-21 hydroxyl group is not essential for steroid binding. Progesterone (with no C-21 OH) bou nd to the greatest extent. Pretreatment of the protein with aspirin to acetylate the free protein amino groups blocked this binding, demonst rating the probability of a Schiff base mechanism. Lens culture studie s with the same three radiolabeled steroids demonstrated much the same result. Rat lenses cultured for 48 hr-11 days, demonstrated that loss of GSH is an early and significant effect of several glucocorticoids (Dex, prednisolone and FML) but is not seen with other non-glucocortic oid steroids. However, none of the steroids tested consistently produc ed lenticular opacification (i.e. cataracts) in this in vitro system, nor did they alter rubidium transport. We suggest that a mechanism oth er than covalent binding of steroids to lens proteins is responsible f or glucocorticoid induced cataracts because: (1) non-glucocorticoids w ere demonstrated to bind lens proteins as well or better than the gluc ocorticoid Dex and (2) only glucocorticoids, and not other steroids, l owered lens reduced glutathione content which has been demonstrated to be associated with other forms of cataract. (C) 1997 Academic Press L imited.