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. 1983 Sep;80(17):5258–5260. doi: 10.1073/pnas.80.17.5258

Transport of glutathione, as gamma-glutamylcysteinylglycyl ester, into liver and kidney.

R N Puri, A Meister
PMCID: PMC384232  PMID: 6577420

Abstract

Administration of gamma-glutamylcysteinylglycyl monomethyl (or monoethyl) ester to mice leads to substantial increases in the levels of glutathione in the liver and kidney. Mice depleted of glutathione by treatment with buthionine sulfoximine, a potent inhibitor of gamma-glutamylcysteine synthetase, exhibited about a 4-fold increase in liver and kidney glutathione levels after administration of glutathione monomethyl ester. This ester also prevented the marked decline in liver glutathione level found after giving mice acetaminophen, and it protected mice from toxicity due to this compound. The findings indicate that the monomethyl and monoethyl esters of glutathione are transported into cells and hydrolyzed to glutathione. Such esters may be useful in experimental work on glutathione metabolism and function and may provide a relatively safe method for protecting cells against damage by toxic compounds, oxygen, and radiation.

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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. 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]
  2. 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]
  3. Gahl W. A., Tietze F., Bashan N., Steinherz R., Schulman J. D. Defective cystine exodus from isolated lysosome-rich fractions of cystinotic leucocytes. J Biol Chem. 1982 Aug 25;257(16):9570–9575. [PubMed] [Google Scholar]
  4. Goldman R. Dipeptide hydrolysis within intact lysosomes in vitro. FEBS Lett. 1973 Jul 1;33(2):208–212. doi: 10.1016/0014-5793(73)80194-2. [DOI] [PubMed] [Google Scholar]
  5. Goldman R., Kaplan A. Rupture of rat liver lysosomes mediated by L-amino acid esters. Biochim Biophys Acta. 1973 Aug 22;318(2):205–216. doi: 10.1016/0005-2736(73)90114-4. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Griffith O. W., Bridges R. J., Meister A. Evidence that the gamma-glutamyl cycle functions in vivo using intracellular glutathione: effects of amino acids and selective inhibition of enzymes. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5405–5408. doi: 10.1073/pnas.75.11.5405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. Griffith O. W., Meister A. Translocation of intracellular glutathione to membrane-bound gamma-glutamyl transpeptidase as a discrete step in the gamma-glutamyl cycle: glutathionuria after inhibition of transpeptidase. Proc Natl Acad Sci U S A. 1979 Jan;76(1):268–272. doi: 10.1073/pnas.76.1.268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hahn R., Wendel A., Flohé L. The fate of extracellular glutathione in the rat. Biochim Biophys Acta. 1978 Mar 20;539(3):324–337. doi: 10.1016/0304-4165(78)90037-5. [DOI] [PubMed] [Google Scholar]
  12. Jensen G. L., Meister A. Radioprotection of human lymphoid cells by exogenously supplied glutathione is mediated by gamma-glutamyl transpeptidase. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4714–4717. doi: 10.1073/pnas.80.15.4714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Meister A. On the cycles of glutathione metabolism and transport. Curr Top Cell Regul. 1981;18:21–58. doi: 10.1016/b978-0-12-152818-8.50009-8. [DOI] [PubMed] [Google Scholar]
  14. Meister A. Selective modification of glutathione metabolism. Science. 1983 Apr 29;220(4596):472–477. doi: 10.1126/science.6836290. [DOI] [PubMed] [Google Scholar]
  15. Reeves J. P. Accumulation of amino acids by lysosomes incubated with amino acid methyl esters. J Biol Chem. 1979 Sep 25;254(18):8914–8921. [PubMed] [Google Scholar]
  16. Steinherz R., Tietze F., Gahl W. A., Triche T. J., Chiang H., Modesti A., Schulman J. D. Cystine accumulation and clearance by normal and cystinotic leukocytes exposed to cystine dimethyl ester. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4446–4450. doi: 10.1073/pnas.79.14.4446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Steinherz R., Tietze F., Raiford D., Gahl W. A., Schulman J. D. Patterns of amino acid efflux from isolated normal and cystinotic human leucocyte lysosomes. J Biol Chem. 1982 Jun 10;257(11):6041–6049. [PubMed] [Google Scholar]
  18. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem. 1969 Mar;27(3):502–522. doi: 10.1016/0003-2697(69)90064-5. [DOI] [PubMed] [Google Scholar]
  19. Williamson J. M., Boettcher B., Meister A. Intracellular cysteine delivery system that protects against toxicity by promoting glutathione synthesis. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6246–6249. doi: 10.1073/pnas.79.20.6246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Williamson J. M., Meister A. Stimulation of hepatic glutathione formation by administration of L-2-oxothiazolidine-4-carboxylate, a 5-oxo-L-prolinase substrate. Proc Natl Acad Sci U S A. 1981 Feb;78(2):936–939. doi: 10.1073/pnas.78.2.936. [DOI] [PMC free article] [PubMed] [Google Scholar]

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