Inhibition of Sorbitol Production in Human Lenses by an Aldose Reductase Inhibitor
Clear and cataractous non-diabetic, human lenses were obtained from eye bank eyes or at the time of routine cataract extraction. Fresh lenses were assayed for glucose, sorbitol, fructose, and aldose reductase and polyol dehydrogenase activities. A significant drop in aldose reductase actvity occurs during cataractogenesis. Clear and cataractous lenses were incubated in either 5.5 mM or 35.5 mM glucose medium with or without the aldose reductase inhibitor AY22,284 (1,3-dioxo-1H-benz-[de]-isoquino-line-2-(3H) acetic acid) present in a final concentration of 4× 10−4 M. In the presence of high glucose, both the clear and cataractous lenses accumulate significant levels of sorbitol, fructose, and a high percentage gain sufficient water to rupture spontaneously. Due to the significant swelling of cataractous lenses in control medium, and the high rate of spontaneous rupture in high-glucose medium it was not possible to correlate the net sorbitol accumulation with the net change in wet weight. The presence of the aldose reductase inhibitor completely blocked net sorbitol accumulation and reduced fructose accumulation. This reduction occurred in the presence of high lenticular glucose levels and unchanged polyol dehydrogenase activity. The similarity of the human and animal lenticular responses to high glucose is striking (van Heyningen 1959a; Chylack & Kinoshita 1969). The relevance of this to’ senile’ cataract formation in diabetics and the promise of aldose reductase inhibitors as a medical treatment for cataracts are discussed.
KeywordsAldose Reductase Glucose Medium Cataract Formation Human Lens Aldose Reductase Inhibitor
Unable to display preview. Download preview PDF.
- Chylack, L.T., Jr.: Classification of human cataracts. Archs. Ophthal (1978) (In Press).Google Scholar
- Epstein, D.L. Reversible unilateral lens opacities in a diabetic patient. Archs. Ophthal. 94: 461–463 (1976).Google Scholar
- Granstrom, K.D. Reflaktionsverauderingen bei diabetes mellitus. Acta Ophthal. 11: 1–160 (1933).Google Scholar
- Hayman, S., Lou, M.F., Merola, L.O. & Kinoshita, J.H. Aldose reductase activity in the lens and other tissues. Biochim. biophys. Acta 128: 474–482 (1966).Google Scholar
- Hockwin, O. & Koch, H.R. Combined noxius influence in Cataract and Abnormalities of the lens. (ed. Bellows, J.G.) Grune and Stratton, New York, 1975, pp. 243–254.Google Scholar
- Kuck, J.F., Jr. Sorbitol pathway metabolites in the diabetic rabbit lens. Invest. Ophthal. 5: 65–74 (1966).Google Scholar
- O’Brien, C.S., Molsberry, J.M. & Allen, J.H. Diabetic cataract incidence and morphology in 126 young diabetic patients. J. Am. med. Ass. 103: 892–897 (1934).Google Scholar
- O’Brien, C.S. & Allen, J.H. Ocular changes in young diabetic patients. J. Am. med. Ass.120: 190–192 (1942).Google Scholar
- Roe, J.H. A colorimetric method for the determination of fructose in blood and urine. J. biol. Chem. 107: 15–22 (1934).Google Scholar
- van Heyningen, R. Metabolism of xylose by the lens. Biochem. J. 73: 197–207 (1959b).Google Scholar