Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Jun;85(6):2009–2013. doi: 10.1172/JCI114666

Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat.

R Kannan 1, J F Kuhlenkamp 1, E Jeandidier 1, H Trinh 1, M Ookhtens 1, N Kaplowitz 1
PMCID: PMC296671  PMID: 1971830

Abstract

Information on the origin of brain glutathione and the possibility of its transport from blood to brain is limited. We found a substantial uptake of 35S-labeled glutathione by the rat brain using the carotid artery injection technique. The brain uptake index of glutathione with and without an irreversible gamma-glutamyl transpeptidase inhibitor, acivicin, was similar. No significant differences in the regional uptake of labeled glutathione were found in rats pretreated with acivicin. The brain uptake index of tracer glutathione was similar to that of cysteine tracer and was lower than that of phenylalanine. The transport of oxidized glutathione (glutathione disfulfide) across the blood-brain barrier was not significantly different from that of sucrose, an impermeable marker. Brain radioactivity 15 s after carotid artery injection of labeled glutathione to rats pretreated with acivicin was predominantly in the form of glutathione. The in vivo glutathione uptake was saturable with an apparent Km of 5.84 mM. Amino acids, amino acid analogues, and other compounds [cysteine, phenylalanine, glutathione disulfide, gamma-glutamylglutamate, gamma-glutamyl p-nitroanilide, 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH)] did not affect glutathione transport. Our data suggest that glutathione is transported across the blood-brain barrier by a saturable and specific mechanism.

Full text

PDF
2009

Selected References

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

  1. Abbott W. A., Bridges R. J., Meister A. Extracellular metabolism of glutathione accounts for its disappearance from the basolateral circulation of the kidney. J Biol Chem. 1984 Dec 25;259(24):15393–15400. [PubMed] [Google Scholar]
  2. 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]
  3. Anderson M. E., Underwood M., Bridges R. J., Meister A. Glutathione metabolism at the blood-cerebrospinal fluid barrier. FASEB J. 1989 Nov;3(13):2527–2531. doi: 10.1096/fasebj.3.13.2572501. [DOI] [PubMed] [Google Scholar]
  4. Bannai S., Kitamura E. Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. J Biol Chem. 1980 Mar 25;255(6):2372–2376. [PubMed] [Google Scholar]
  5. Bulter J., Spielberg S. P., Schulman J. D. Reduction of disulfide-containing amines amino acids, and small peptides. Anal Biochem. 1976 Oct;75(2):674–675. doi: 10.1016/0003-2697(76)90129-9. [DOI] [PubMed] [Google Scholar]
  6. Cornford E. M., Braun L. D., Crane P. D., Oldendorf W. H. Blood-brain barrier restriction of peptides and the low uptake of enkephalins. Endocrinology. 1978 Oct;103(4):1297–1303. doi: 10.1210/endo-103-4-1297. [DOI] [PubMed] [Google Scholar]
  7. Dawson J. R., Vähäkangas K., Jernström B., Moldéus P. Glutathione conjugation by isolated lung cells and the isolated, perfused lung. Effect of extracellular glutathione. Eur J Biochem. 1984 Feb 1;138(3):439–443. doi: 10.1111/j.1432-1033.1984.tb07935.x. [DOI] [PubMed] [Google Scholar]
  8. Ermisch A., Rühle H. J., Landgraf R., Hess J. Blood-brain barrier and peptides. J Cereb Blood Flow Metab. 1985 Sep;5(3):350–357. doi: 10.1038/jcbfm.1985.49. [DOI] [PubMed] [Google Scholar]
  9. Fariss M. W., Reed D. J. High-performance liquid chromatography of thiols and disulfides: dinitrophenol derivatives. Methods Enzymol. 1987;143:101–109. doi: 10.1016/0076-6879(87)43018-8. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Hagen T. M., Aw T. Y., Jones D. P. Glutathione uptake and protection against oxidative injury in isolated kidney cells. Kidney Int. 1988 Jul;34(1):74–81. doi: 10.1038/ki.1988.147. [DOI] [PubMed] [Google Scholar]
  12. Kaplowitz N., Aw T. Y., Ookhtens M. The regulation of hepatic glutathione. Annu Rev Pharmacol Toxicol. 1985;25:715–744. doi: 10.1146/annurev.pa.25.040185.003435. [DOI] [PubMed] [Google Scholar]
  13. Kilberg M. S., Christensen H. N., Handlogten M. E. Cysteine as a system-specific substrate for transport system ASC in rat hepatocytes. Biochem Biophys Res Commun. 1979 May 28;88(2):744–751. doi: 10.1016/0006-291x(79)92110-7. [DOI] [PubMed] [Google Scholar]
  14. Lash L. H., Jones D. P. Renal glutathione transport. Characteristics of the sodium-dependent system in the basal-lateral membrane. J Biol Chem. 1984 Dec 10;259(23):14508–14514. [PubMed] [Google Scholar]
  15. Lash L. H., Jones D. P. Transport of glutathione by renal basal-lateral membrane vesicles. Biochem Biophys Res Commun. 1983 Apr 15;112(1):55–60. doi: 10.1016/0006-291x(83)91796-5. [DOI] [PubMed] [Google Scholar]
  16. Lauterburg B. H., Adams J. D., Mitchell J. R. Hepatic glutathione homeostasis in the rat: efflux accounts for glutathione turnover. Hepatology. 1984 Jul-Aug;4(4):586–590. doi: 10.1002/hep.1840040402. [DOI] [PubMed] [Google Scholar]
  17. Makowske M., Christensen H. N. Contrasts in transport systems for anionic amino acids in hepatocytes and a hepatoma cell line HTC. J Biol Chem. 1982 May 25;257(10):5663–5670. [PubMed] [Google Scholar]
  18. 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]
  19. Oldendorf W. H. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol. 1971 Dec;221(6):1629–1639. doi: 10.1152/ajplegacy.1971.221.6.1629. [DOI] [PubMed] [Google Scholar]
  20. Oldendorf W. H. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res. 1970 Dec 1;24(2):372–376. doi: 10.1016/0006-8993(70)90123-x. [DOI] [PubMed] [Google Scholar]
  21. Ookhtens M., Hobdy K., Corvasce M. C., Aw T. Y., Kaplowitz N. Sinusoidal efflux of glutathione in the perfused rat liver. Evidence for a carrier-mediated process. J Clin Invest. 1985 Jan;75(1):258–265. doi: 10.1172/JCI111682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pardridge W. M. Neuropeptides and the blood-brain barrier. Annu Rev Physiol. 1983;45:73–82. doi: 10.1146/annurev.ph.45.030183.000445. [DOI] [PubMed] [Google Scholar]
  23. Pardridge W. M., Oldendorf W. H. Kinetics of blood-brain transport of hexoses. Biochim Biophys Acta. 1975 Mar 25;382(3):377–392. doi: 10.1016/0005-2736(75)90279-5. [DOI] [PubMed] [Google Scholar]
  24. Raps S. P., Lai J. C., Hertz L., Cooper A. J. Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons. Brain Res. 1989 Jul 31;493(2):398–401. doi: 10.1016/0006-8993(89)91178-5. [DOI] [PubMed] [Google Scholar]
  25. Richman P. G., Meister A. Regulation of gamma-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem. 1975 Feb 25;250(4):1422–1426. [PubMed] [Google Scholar]
  26. Sage J. I., Duffy T. E. Pentobarbital anesthesia: influence on amino acid transport across the blood-brain barrier. J Neurochem. 1979 Oct;33(4):963–965. doi: 10.1111/j.1471-4159.1979.tb09930.x. [DOI] [PubMed] [Google Scholar]
  27. Sekura R., Meister A. Glutathione turnover in the kidney; considerations relating to the gamma-glutamyl cycle and the transport of amino acids. Proc Natl Acad Sci U S A. 1974 Aug;71(8):2969–2972. doi: 10.1073/pnas.71.8.2969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Slivka A., Mytilineou C., Cohen G. Histochemical evaluation of glutathione in brain. Brain Res. 1987 Apr 21;409(2):275–284. doi: 10.1016/0006-8993(87)90712-8. [DOI] [PubMed] [Google Scholar]
  29. Szasz G. A kinetic photometric method for serum gamma-glutamyl transpeptidase. Clin Chem. 1969 Feb;15(2):124–136. [PubMed] [Google Scholar]
  30. Wade L. A., Brady H. M. Cysteine and cystine transport at the blood-brain barrier. J Neurochem. 1981 Sep;37(3):730–734. doi: 10.1111/j.1471-4159.1982.tb12548.x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES