Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 Nov;86(22):8727–8731. doi: 10.1073/pnas.86.22.8727

Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

J Mårtensson 1, R Steinherz 1, A Jain 1, A Meister 1
PMCID: PMC298361  PMID: 2813421

Abstract

Treatment of newborn rats and mice with buthionine sulfoximine, an inhibitor of glutathione synthesis, leads to development of cataracts, which are not prevented by treatment with glutathione, but they are prevented by treatment with glutathione monoester. Cataracts are associated with glutathione deficiency in the lens epithelium, which undergoes severe degeneration. The findings indicate that glutathione normally functions in the protection of the lens and lens epithelium against oxidative injury, suggesting that procedures that increase lens glutathione levels might be useful for prevention of other types of cataracts. Relatively low doses of buthionine sulfoximine produce cataracts in newborn animals, and treatment of pregnant mice with buthionine sulfoximine during the last part of gestation leads to cataract formation in the offspring. The high sensitivity of the developing lens to the effects of glutathione deficiency suggests that this tissue may be a useful model for studies on glutathione function.

Full text

PDF
8730

Images in this article

8729Image
on p.8729
8729Image
on p.8729
8730Image
on p.8730
8730Image
on p.8730
8730Image
on p.8730
8730Image
on p.8730

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson M. E., Meister A. Glutathione monoesters. Anal Biochem. 1989 Nov 15;183(1):16–20. doi: 10.1016/0003-2697(89)90164-4. [DOI] [PubMed] [Google Scholar]
  2. Anderson M. E., Meister A. Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis. Proc Natl Acad Sci U S A. 1983 Feb;80(3):707–711. doi: 10.1073/pnas.80.3.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson M. E., Powrie F., Puri R. N., Meister A. Glutathione monoethyl ester: preparation, uptake by tissues, and conversion to glutathione. Arch Biochem Biophys. 1985 Jun;239(2):538–548. doi: 10.1016/0003-9861(85)90723-4. [DOI] [PubMed] [Google Scholar]
  4. BELLOWS J. G., SHOCH D. E. Alloxan diabetes and the lens. Am J Ophthalmol. 1950 Oct;33(10):1555–1564. doi: 10.1016/0002-9394(50)91216-5. [DOI] [PubMed] [Google Scholar]
  5. Boveris A., Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J. 1973 Jul;134(3):707–716. doi: 10.1042/bj1340707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. COHEN A. I. Electron microscopic observations on the lens of the neonatal albino mouse. Am J Anat. 1958 Sep;103(2):219–245. doi: 10.1002/aja.1001030205. [DOI] [PubMed] [Google Scholar]
  7. Calvin H. I., Medvedovsky C., Worgul B. V. Near-total glutathione depletion and age-specific cataracts induced by buthionine sulfoximine in mice. Science. 1986 Aug 1;233(4763):553–555. doi: 10.1126/science.3726547. [DOI] [PubMed] [Google Scholar]
  8. Dethlefsen L. A., Biaglow J. E., Peck V. M., Ridinger D. N. Toxic effects of extended glutathione depletion by buthionine sulfoximine on murine mammary carcinoma cells. Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1157–1160. doi: 10.1016/0360-3016(86)90248-8. [DOI] [PubMed] [Google Scholar]
  9. Dethmers J. K., Meister A. Glutathione export by human lymphoid cells: depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7492–7496. doi: 10.1073/pnas.78.12.7492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Epstein D. L., Kinoshita J. H. The effect of diamide on lens glutathione and lens membrane function. Invest Ophthalmol. 1970 Aug;9(8):629–638. [PubMed] [Google Scholar]
  11. Garner M. H., Spector A. Selective oxidation of cysteine and methionine in normal and senile cataractous lenses. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1274–1277. doi: 10.1073/pnas.77.3.1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Garner W. H., Garner M. H., Spector A. Gamma-crystallin, a major cytoplasmic polypeptide disulfide linked to membrane proteins in human cataract. Biochem Biophys Res Commun. 1981 Jan 30;98(2):439–447. doi: 10.1016/0006-291x(81)90859-7. [DOI] [PubMed] [Google Scholar]
  13. Giblin F. J., Chakrapani B., Reddy V. N. Glutathione and lens epithelial function. Invest Ophthalmol. 1976 May;15(5):381–393. [PubMed] [Google Scholar]
  14. Giblin F. J., Chakrapani B., Reddy V. N. The effects of X-irradiation on lens reducing systems. Invest Ophthalmol Vis Sci. 1979 May;18(5):468–475. [PubMed] [Google Scholar]
  15. Goosey J. D., Zigler J. S., Jr, Kinoshita J. H. Cross-linking of lens crystallins in a photodynamic system: a process mediated by singlet oxygen. Science. 1980 Jun 13;208(4449):1278–1280. doi: 10.1126/science.7375939. [DOI] [PubMed] [Google Scholar]
  16. Griffith O. W., Anderson M. E., Meister A. Inhibition of glutathione biosynthesis by prothionine sulfoximine (S-n-propyl homocysteine sulfoximine), a selective inhibitor of gamma-glutamylcysteine synthetase. J Biol Chem. 1979 Feb 25;254(4):1205–1210. [PubMed] [Google Scholar]
  17. Griffith O. W. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem. 1982 Nov 25;257(22):13704–13712. [PubMed] [Google Scholar]
  18. Griffith O. W., Meister A. Glutathione: interorgan translocation, turnover, and metabolism. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5606–5610. doi: 10.1073/pnas.76.11.5606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Griffith O. W., Meister A. Origin and turnover of mitochondrial glutathione. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4668–4672. doi: 10.1073/pnas.82.14.4668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Griffith O. W., Meister A. Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem. 1979 Aug 25;254(16):7558–7560. [PubMed] [Google Scholar]
  21. Harding J. J. Free and protein-bound glutathione in normal and cataractous human lenses. Biochem J. 1970 May;117(5):957–960. doi: 10.1042/bj1170957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Harris C., Fantel A. G., Juchau M. R. Differential glutathione depletion by L-buthionine-S,R-sulfoximine in rat embryo versus visceral yolk sac in vivo and in vitro. Biochem Pharmacol. 1986 Dec 15;35(24):4437–4441. doi: 10.1016/0006-2952(86)90760-4. [DOI] [PubMed] [Google Scholar]
  23. Harris C., Namkung M. J., Juchau M. R. Regulation of intracellular glutathione in rat embryos and visceral yolk sacs and its effect on 2-nitrosofluorene-induced malformations in the whole embryo culture system. Toxicol Appl Pharmacol. 1987 Mar 30;88(1):141–152. doi: 10.1016/0041-008x(87)90278-x. [DOI] [PubMed] [Google Scholar]
  24. KINSEY V. E., MERRIAM F. C. Studies on the crystalline lens. II. Synthesis of glutathione in the normal and cataractous rabbit lens. AMA Arch Ophthalmol. 1950 Sep;44(3):370–380. [PubMed] [Google Scholar]
  25. Lambert G. H., Thorgeirsson S. S. Glutathione in the developing mouse liver--I. Developmental curve and depletion after acetaminophen treatment. Biochem Pharmacol. 1976 Aug 1;25(15):1777–1781. doi: 10.1016/0006-2952(76)90415-9. [DOI] [PubMed] [Google Scholar]
  26. Meister A., Anderson M. E. Glutathione. Annu Rev Biochem. 1983;52:711–760. doi: 10.1146/annurev.bi.52.070183.003431. [DOI] [PubMed] [Google Scholar]
  27. Mårtensson J., Jain A., Frayer W., Meister A. Glutathione metabolism in the lung: inhibition of its synthesis leads to lamellar body and mitochondrial defects. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5296–5300. doi: 10.1073/pnas.86.14.5296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mårtensson J., Meister A. Mitochondrial damage in muscle occurs after marked depletion of glutathione and is prevented by giving glutathione monoester. Proc Natl Acad Sci U S A. 1989 Jan;86(2):471–475. doi: 10.1073/pnas.86.2.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nedergaard J., Cannon B. Overview--preparation and properties of mitochondria from different sources. Methods Enzymol. 1979;55:3–28. doi: 10.1016/0076-6879(79)55003-4. [DOI] [PubMed] [Google Scholar]
  30. PIRIE A., VAN HEYNINGEN R., BOAG J. W. Changes in lens during the formation of x-ray cataract in rabbits. Biochem J. 1953 Jul;54(4):682–688. doi: 10.1042/bj0540682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Puri R. N., Meister A. Transport of glutathione, as gamma-glutamylcysteinylglycyl ester, into liver and kidney. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5258–5260. doi: 10.1073/pnas.80.17.5258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Reddy V. N., Giblin F. J. Metabolism and function of glutathione in the lens. Ciba Found Symp. 1984;106:65–87. doi: 10.1002/9780470720875.ch5. [DOI] [PubMed] [Google Scholar]
  33. Reddy V. N. Metabolism of glutathione in the lens. Exp Eye Res. 1971 May;11(3):310–328. doi: 10.1016/s0014-4835(71)80043-x. [DOI] [PubMed] [Google Scholar]
  34. Reddy V. N., Varma S. D., Chakrapani B. Transport and metabolism of glutathione in the lens. Exp Eye Res. 1973 Jun;16(2):105–114. doi: 10.1016/0014-4835(73)90305-9. [DOI] [PubMed] [Google Scholar]
  35. Redinbaugh M. G., Turley R. B. Adaptation of the bicinchoninic acid protein assay for use with microtiter plates and sucrose gradient fractions. Anal Biochem. 1986 Mar;153(2):267–271. doi: 10.1016/0003-2697(86)90091-6. [DOI] [PubMed] [Google Scholar]
  36. Singhal R. K., Anderson M. E., Meister A. Glutathione, a first line of defense against cadmium toxicity. FASEB J. 1987 Sep;1(3):220–223. doi: 10.1096/fasebj.1.3.2887478. [DOI] [PubMed] [Google Scholar]
  37. Slott V. L., Hales B. F. Effect of glutathione depletion by buthionine sulfoximine on rat embryonic development in vitro. Biochem Pharmacol. 1987 Mar 1;36(5):683–688. doi: 10.1016/0006-2952(87)90719-2. [DOI] [PubMed] [Google Scholar]
  38. Spector A., Garner W. H. Hydrogen peroxide and human cataract. Exp Eye Res. 1981 Dec;33(6):673–681. doi: 10.1016/s0014-4835(81)80107-8. [DOI] [PubMed] [Google Scholar]
  39. Spector A. The search for a solution to senile cataracts. Proctor lecture. Invest Ophthalmol Vis Sci. 1984 Feb;25(2):130–146. [PubMed] [Google Scholar]
  40. Wellner V. P., Anderson M. E., Puri R. N., Jensen G. L., Meister A. Radioprotection by glutathione ester: transport of glutathione ester into human lymphoid cells and fibroblasts. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4732–4735. doi: 10.1073/pnas.81.15.4732. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES