Mechanism of cataract production by 3- β(2-diethylaminoethoxy) androst-5-en-17-one hydrochloride, U18666A: An inhibitor of cholesterol biosynthesis

Abstract

The present report describes a new model for cataract research induced by a compound (3-β(2-diethylaminoethoxy) androst-5-en-17-one hydrochloride; i.e. U18666A) which inhibits the enzymatic reduction of desmosterol to cholesterol and provides information on the possible mechanism of cataractogenesis. Treatment of the new born rat with U18666A results in nuclear cataracts appearing between 15 and 25 days of age. This cataract is apparently unrelated to accumulation of desmosterol, since this sterol was not detected in opaque lenses until long after their first appearance. Rather, development of this opacity could involve a selective reduction in the concentrations of γ-crystallin, the smallest of the four classes of water-soluble crystallins and the single major constituent of the rat lens after water. The observed lowering of γ-crystallin levels in opaque lens is apparently explained by a differential reduction in protein synthesis measured from [ 3H]leucine injected intraocularly. This differential effect could be explained by marked changes in the intracellular concentration of Na + and K + ions in opaque lens; Na + levels greatly increased and K + decreased. Recent reports indicate that decreasing the intracellular ratio of K + Na + in lens results in a shift of protein synthesis from lower to higher molecular weight species. In view of this information and the results of the present study, we suggest that the development and/or progression of the cataracts induced by U18666A could be related to a selective block in formation of γ-crystallin secondary to alteration in the levels of Na + and K + ions in lens.