NUTRACEUTICALS Editors: Gil Hardy, PhDErick Valencia, MD

Glutathione—Nutritional and PharmacologicViewpoints: Part I

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

This article will be presented in six parts, insix consecutive issues, through the end ofthe year 2001.—Editor

L iving organisms require sulphur. Someof them (sulfur bacteria) use it as a freeelement, some (plants) as sulfate or

sulfide, and some (higher animals) as thecysteine and methionine residues ofproteins.

Irrespective of which form is ingested,sulphur occurs in cells in three principalchemical fractions, that are to some extentinterconvertible. One of these is the sulfidefraction, which is made up of2S-CH3

groups from methionine residues of cellularproteins. The second sulfur fraction occursas an ester or amide sulfate in various poly-saccharides and steroids. The third sulfhurfraction is present as cellular sulfhydryl(SH) and disulfide (SS) groups. This frac-tion has been the one most amenable toinvestigation, chiefly due to a multitude ofmethods available for detecting and assay-ing these groups. In consequence, there isa welter of factual knowledge about themand their potential for clinical pharmaco-nutrition, much of it obtained over thepast 20 y.

HISTORY

Interest in the subject originates from 1810when Wollaston1 isolated the SS-containingamino acid cysteine from a urinary calculus.Another 74 y elapsed before the first thiolwas obtained,2 but shortly afterward othersulfur-containing substances, including animpure form of glutathione (GSH), was rec-ognized by Rey Pailhade who proposed thename philothione.3 Soon afterward, Mor-ner4 discovered that cysteine results fromthe hydrolysis of proteins. It was much later,when precautions had been taken to preventautoxidation during proteolysis and meth-ods had been developed for assaying

protein-SH groups, before it was realizedthat this cysteine could arise from the pres-ence in proteins of cysteine as well as cys-teine residues.

The source of the non–protein-SHgroups was eventually identified by Hop-kins, whose discovery and isolation of GSHin 1921 put the study of SH groups on a firmchemical footing, thus stimulating a greatand sustained biochemical interest.

A puzzling dietary problem was posedafter the discovery of methionine in 19225

when it was realized that methionine resi-dues in proteins are the source of much ofthe sulfur of SH and SS groups. This wasnot resolved until 1942, when DuVigneaud18 showed how methionine canserve as a methylating agent and how theresulting homocysteine can be converted tocysteine.

The idea that thiols as a group mighthave some common biologic functionsprang from the discovery, first reportedwith sea urchin eggs by Rapkine in 1931,6

that SH-group concentrations change duringmitosis. This finding confirmed the exis-tence of an SH/SS cycle and focused atten-tion on the most abundant of thiols, namelyGSH.

In a celebrated review in 1951, Baron,7

by extrapolating from these properties andusing the data of Rapkine, put forward theidea that stimulation of SH-enzyme activi-ties by GSH also occurs intracellularly andis “one of the regulatory mechanisms ofcellular respiration.”

The main research on GSH during the1960s and 1970s was by Krebs, Hems, andVina in the Metabolic Research Laboratory,Oxford. In 1978 they published the regula-tion of the hepatic concentration of reducedGSH and the maintenance of GSH contentin isolated hepatocytes.8,9 Subsequently,different groups around the world includingourselves have demonstrated that GSH isreduced under stress in animals and humanresearch studies.10–17

SUMMARY

GSH is a tripeptide made up of glycine,glutamic acid, and cysteine that is synthe-sized intracellularly and plays a vital role in

protecting cells against the toxic effect ofreactive oxygen species. Endogenous GSHsynthesis depends on stores of cysteine, glu-tamine, ornithine, proline, and glutamate indifferent organs such as muscle, liver, lung,kidney, immune cells, red cells, and gastro-intestinal tract. Under stress, GSH turnoverincreases as a defense mechanism againstfree radicals produced by infections, hypo-perfusion, ischemia, and reperfusion. Exog-enous GSH might be useful in increasing invivo concentrations in a wide variety ofpathologies. Pharmaconutrition with GSHas an ester or sodium salt, precursors such asN-acetyl-cysteine, L-2-oxothiazolidine-4-carboxylic acid,18 and other amino acidsfrom foods may play an important role infuture medical treatments.

REFERENCES

1. Wollaston WH. De l’oxide cystique, espe`ce nou-velle de calcul. Ann Chim 1810;76:21

2. Baumann E. Ueber Cystin und Cystein. Hoppe-Seyler Z Physiol Chem 1884;8:299

3. De Rey Pailhade J. Sur un corps d’origine organiquehydrogenant le soufre a froid. Compt Rendu 1888;106:1683

4. Morner KAH. Cystin, ein Spaltungsprodukt derHornsubstanz. Hoppe-Seyler Z Physiol Chem 1988;28:595

5. Mueller JH. A new sulphur-containing amino acidisolated from casein. Proc Soc Exp Biol Med 1922;19:161

6. Rapkine L. Sur les processus chimiques au cours dela division cellulaire. Ann Physiol Phys Chim Biol1931;9:383

7. Barron ESG. Thiol groups of biological importance.Adv Enzymol 1951;11:201

8. Krebs HA, Hems R, Vin˜a J. Regulation of the he-patic concentration of reduced glutathione. In: SiesH, Wendel A, eds. Funcion of glutathione in liverand kidney. Berlin: Springer-Verlag, 1978:8

9. Vina J, Hems R, Krebs H. Maintenance of glutathi-one content in isolated hepatocytes. Biochem J1978;170:627

10. Meister A, Anderson ME. Glutathione. Annu RevBiochem 1983;52:711

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

12. Keller GA, Barke R, Harty JT, et al. Decreasedhepatic glutathione levels in septic shock. Arch Surg1985;120:941

13. Stein HJ, Hinder RA, Oosthuizen MMJ. Gastric

Correspondence to: Gil Hardy, PhD, FRSC, Ox-ford Brookes University, School of Biologicaland Molecular Sciences, Gipsy Lane, OxfordOX3 0BP, UK. E-mail: ghardy@nutrinox.com

Nutrition 17:428–429, 2001 0899-9007/01/$20.00©Elsevier Science Inc., 2001. Printed in the United States. All rights reserved. PII S0899-9007(01)00531-7

mucosal injured caused by hemorrhagic shock andreperfusion: protective role of the antioxidant gluta-thione. Surgery 1990;108:467

14. Hong RW, Round JD, Helton WS, Robinson MK,Wilmore DW. Glutamine preserves liver glutathi-one after lethal hepatic injury. Ann Surg 1992;215:114

15. Bianchi G, Bugianesi E, Ronchi M, et al. Glutathi-one kinetics in normal man and in patients with livercirrhosis. J Hepatol 1997;26:606

16. Hammarqvist F, Luo J, Cotgreave IA, Anderson K,Wernerman J. Skeletal muscle glutathione is de-pleted in critically ill patients. Crit Care Med 1997;25:78

17. Luo J, Hammarqvist F, Anderson K, WernermanJ. Surgical trauma decreases glutathione syntheticcapacity in human skeletal muscle tissue. Am JPhysiol 1998;275:E359

18. Exner R, Wessner B, Manhart N, Roth E. Therapeu-tic potential of glutathione. Wein Klin Wochenschr2000;112:610

Nutrition Volume 17, Number 5, 2001 429Glutathione—Nutritional and Pharmacologic Viewpoints