Inhibition of Sorbitol Production in Human Lenses by an Aldose Reductase Inhibitor

  • Leo T. ChylackJr.
  • Horace F. HenriquesIII
  • William H. Tung
Part of the Documenta Ophthalmologica Proceedings Series book series (DOPS, volume 18)

Abstract

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.

Keywords

Sugar Phenol Bicarbonate Xylose Fructose 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Chylack, L.T., Jr.: Classification of human cataracts. Archs. Ophthal (1978) (In Press).Google Scholar
  2. Chylack, L.T., Jr. & Kinoshita, J.H. A biochemical evaluation of a cataract induced in a high-glucose medium. Invest. Ophthal. 8: 401–412 (1969).PubMedGoogle Scholar
  3. Chylack, L.T., Jr. Mechanism of ‘hypoglycemic’ cataract formation in the rat lens. I. The role of hexokinase instability. Invest. Ophthal. 14: 746–755 (1975).PubMedGoogle Scholar
  4. Dvornik, D., Simmard-Duquesene, N., Krami, M., Sestang, K., Gabbay, K.H. & Kinoshita, J.H. Polyol accumulation in galactosemic and diabetic rats: Control an aldose reductase inhibitor. Science, N. Y. 182: 1146–1148 (1973).CrossRefGoogle Scholar
  5. Epstein, D.L. Reversible unilateral lens opacities in a diabetic patient. Archs. Ophthal. 94: 461–463 (1976).Google Scholar
  6. Granstrom, K.D. Reflaktionsverauderingen bei diabetes mellitus. Acta Ophthal. 11: 1–160 (1933).Google Scholar
  7. 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
  8. 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
  9. Kinoshita, J.H., Merola, L.O. & Dikmak, E. Osmotic changes in experimental galactose cataracts. Expl. Eye Res. 1: 405–410 (1962).CrossRefGoogle Scholar
  10. Kinoshita, J.H. & Merola, L.O. Hydration of the lens during the development of galactose cataract. Invest. Ophthal. 3: 577–584 (1964).PubMedGoogle Scholar
  11. Kuck, J.F., Jr. Sorbitol pathway metabolites in the diabetic rabbit lens. Invest. Ophthal. 5: 65–74 (1966).Google Scholar
  12. Lowry, O.H., Rosebrough, N.J., Farr, A.L. & Randall, R.J. Protein measurement with the Folin-phenol reagent. J. biol. Chem. 193: 265–275 (1951).PubMedGoogle Scholar
  13. 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
  14. O’Brien, C.S. & Allen, J.H. Ocular changes in young diabetic patients. J. Am. med. Ass.120: 190–192 (1942).Google Scholar
  15. Pirie, A. & van Heyningen, R. The effect of diabetes on the content of sorbitol, glucose, fructose and inositol in the human lens. Expl. Eye Res. 3: 124–131 (1964).CrossRefGoogle Scholar
  16. Roe, J.H. A colorimetric method for the determination of fructose in blood and urine. J. biol. Chem. 107: 15–22 (1934).Google Scholar
  17. van Heyingen, R. Formation of polyols by the lens of the rat with ‘sugar’ cataract. Nature 184: 194–195 (1959a).CrossRefGoogle Scholar
  18. van Heyningen, R. Metabolism of xylose by the lens. Biochem. J. 73: 197–207 (1959b).Google Scholar
  19. Varma, S.D. & Kinoshita, J.H. Sorbitol pathway in diabetic and galactosemic rat lens. Biochim. biophys. Acta 338: 632–640 (1974).CrossRefGoogle Scholar
  20. Varma, S.D. & Kinoshita, J.H. Inhibition of lens aldose reductase by flavonoids — their possible role in the prevention of diabetic cataracts. Biochem. Pharmac. 25: 2505–2513 (1976).CrossRefGoogle Scholar
  21. Varma, S.D., Mizuno, A. & Kinoshita, J.H. Diabetic cataracts and flavonoids. Science 195: 205–206 (1977).CrossRefPubMedGoogle Scholar
  22. West, C.D. & Rapoport, S. Modification of colorimetric method for determination of mannitol and sorbitol in plasma and urine. Proc. Soc. exp. Biol. Med. 70: 141–146 (1949).PubMedGoogle Scholar

Copyright information

© Dr W. Junk b.v. Publishers 1979

Authors and Affiliations

  • Leo T. ChylackJr.
    • 1
    • 2
  • Horace F. HenriquesIII
    • 1
    • 2
  • William H. Tung
    • 1
    • 2
  1. 1.BostonUSA
  2. 2.Howe Laboratory of OphthalmologyHarvard Medical School and the Massachusetts Eye & Ear InfirmaryBostonUSA

Personalised recommendations