NUTRACEUTICALS Editors: Gil Hardy, PhDErick Valencia, MD

Glutathione—Nutritional and PharmacologicalViewpoints: Part III

Erick Valencia, MD, Angela Marin, RD and Gil Hardy, PhD, FRSCFrom Medellin, Colombia; and the Pharmaceutical Nutrition Group, School of Biological

and Molecular Sciences, Oxford Brookes University, Oxford, United Kingdom

PHYSIOLOGY

Normal Metabolism of Glutathione

Glutathione (GSH) is in a constant state ofmetabolic turnover. Because it is activelysynthesized, it also must be degraded. Thebody has the capacity to synthesize GSHfrom cysteine, methionine, glutamate, andGSH obtained from foods. The amino acidsare taken up by the liver to increase liverGSH, which then detoxifies diverse procar-cinogens, chemical toxins, and free radicalsthrough its function as a cosubstrate for theGSH S-transferases and the GSH-dependentperoxidases. In liver, GSH is secreted notonly across hepatocyte membranes to ve-nous sinusoids but also across the canalicu-lar membrane into bile.1–4 Hepatic GSHsynthesis and venous efflux likely contrib-ute to the sustained elevation in plasma,kidney,5,6 muscle, red cells,7 lymphoidcells,8 and other organs (heart, lung, brain,intestine, etc.). Biliary efflux may serve sev-eral important functions in the intestine.First, because low intestinal GSH contentcaused by inhibition of GSH synthesis isassociated with intestinal lesions,9 GSHmay be required for normal intestinal func-tion. Second, biliary GSH can be taken upacross the intestinal brush border10,11 andused in the detoxication of fatty-acid hy-droperoxides in intestinal epithelium.12,13

Third, delivery of GSH and other thiols ordisulfides by bile may help maintain luminalthiol-disulfide balance and regulate en-zymes on the intestinal brush border thatcontain a critical thiol14,15Fourth, GSH maybe important in the absorption of iron16,17

and trace elements such as selenium frominorganic selenite18 (Fig. 1).

Metabolism of Glutathione Under Stress

During fasting, energy is drawn from fat,protein, and glycogen stores.19 Approxi-

mately 30 g of glucose per day can be drawnfrom glycogen stores in liver and muscle,although the glucose requirements of thebrain alone are 90 g/d. The balance is pro-vided from hepatic gluconeogenesis, a pro-cess that uses amino acids from the break-down of muscle (alanine, glutamine, andcysteine), glycerol from lipolysis of fatstores, and lactate and pyruvate from othertissue sources. In the early stages of fastingand stress, supplies of glutamine, cysteine,and methionine are interrupted, and GSHliver concentrations depend not only onGSSG, which can be converted to GSH byglutathione reductase, but also on cysteineand glutamine stores from muscle and intes-tinal organs. As a result of these stores,GSH delivery from liver increases to protectdifferent organs from oxidative stress. Asstarvation progresses, GSH production de-

creases according to the body’s redox sta-tus20,21 (Fig. 2).

REFERENCES

1. Bartoli GM, Sies H. Reduced and oxidated glutathi-one efflux from liver. FEBS Lett 1978;86:89

2. Inoue M, Kinne R, Tran T, Arias IM. Glutathionetransport across hepatocyte plasma membranes:analysis using isolated rat-liver sinusoidal-membrane vesicles. Eur J Biochem 1984;138:491

3. Lindwall G, Boyer TD. Excretion of glutathioneconjugates by primary cultured rat hepatocytes.J Biol Chem 1987;262:5151

4. Ookhtens M, Lyon I, Fernandez-Checa J, KaplowitzN. Inhibition of glutathione efflux in the perfused ratliver and isolated hepatocytes by organic anions andbilirubin. Kinetics, sidedness, and molecular forma.J Clin Invest 1988;82:608

Correspondence to: Erick Valencia, MD, OxfordBrookes University, Gipsy Lane Campus, Heading-ton, Oxford OX3 0BP, UK. E-mail: evalencia@brookes.ac.uk

FIG. 1. Normal metabolism of glutathione.21,22 Fe11, iron; GSH, glutathione; Se, selenium.

Nutrition 17:696–697, 2001 0899-9007/01/$20.00©Elsevier Science Inc., 2001. Printed in the United States. All rights reserved. PII S0899-9007(01)00606-2

5. Lash LH, Jones DP. Transport of glutathione byrenal basal–lateral membrane vesicles. BiochemBiophys Res Commun 1983;112:55

6. Lash LH, Jones DP. Renal glutathione transport.J Biol Chem 1984;259:14508

7. Dimant E, Landberg E, London IM. The metabolicbehaviour of reduced glutathione in human andavian erythrocytes. J Biol Chem 1955;213:769

8. Griffith OW, Novogrodsky A, Meister A. Translo-

cation of glutathione from lymphoid cells that havemarkedly different gama-glutamyl transpeptidase ac-tivities. Proc Natl Acad Sci USA 1979;76:2249

9. Martensson J, Jain A, Meister A. Glutathione isrequired for intestinal function. Proc Natl Acad SciUSA 1990;87:1715

10. Hagen TM, Jones DP. Transepithelial transport ofglutathione in vascular perfused small intestine ofrat. Am J Physiol 1987;252:G607

11. Vincenzini MT, Favilli F, Iantomasi T. Intestinaluptake and transmembrane transport systems of in-tact GSH: characteristics and possible biologicalrole. Biochim Biophys Acta 1992;1113:13

12. Aw TY, Williams MW, Gray L. Absorption andlymphatic transport of peroxidized lipids by ratsmall intestine in vivo: role of mucosal GSH. Am JPhysiol 1992;262:G99

13. Kowalski DP, Feeley RM, Jones DP. Use of exog-enous glutathione for metabolism of peroxidizedmethyl linoleate in rat small intestine. J Nutr 1990;120:1115

14. Gilbert HF. Thermodynamic and kinetic constraintson thiol/disulfide exchange involving glutathione re-dox buffers. In: Taniguchi N, Higashi T, SakamotoY, Meister A, eds.Glutathione centennial. Molecu-lar perspectives and clinical implications.San Di-ego: Academic Press, 1989:73

15. Ziegler DM. Role of reversible oxidation-reductionof enzyme thiol-disulfides in metabolic regulation.Annu Rev Biochem 1985;54:305

16. Kapsokefalou M, Miller DD. Effect of meat andselected food components on the valence of non-heme iron during in vitro digestion. J Food Sci1991;56:352

17. Layrisse M, Martinez-Torres C, Leets I, Taylor P,Ramirez J. Effect of histidine, cysteine, glutathioneor beef on iron absorption in humans. J Nutr 1984;114:217

18. Scharrer E, Senn E, Wolffram S. Stimulation ofmucosal uptake of selenium from selenite by somethiols at various sites of rat intestine. Biol TraceElem Res 1992;33:109

19. Chaill GF. Starvation in man. Clin EndocrinolMetab 1976;5:397

20. Lauterburg BH, Adams JD, Mitchell JR. Hepaticglutathione homeostasis in rats: efflux accounts forglutathione turnover. Hepatology 1984;4:584

21. Lyons J, Rauh-Pfeiffer A, Yu YM, Lu XM, Zura-kowski D, Topkins RG, Ajami AM, Young VR,Castillo L. Blood glutathione synthesis rates inhealthy adults receiving a sulphur amino-acid freediet. Proc Natl Acad Sci USA 2000;97:5071

22. Malmezat T, Breuille D, Capitan P, Mirand PP,Obled C. Glutathione turnover is increased duringthe acute phase of sepsis in rats. J Nutri 2000;130:1239

FIG. 2. Metabolism of glutathione under stress. GSH, glutathione; GSSG, oxidized glutathione; GR,glutathione reductase; TPN, total parenteral nutrition.20,23

Nutrition Volume 17, Numbers 7/8, 2001 697Glutathione—Part III