Glutathione Metabolism and Its Implications for Health

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The Journal of Nutritionjn.nutrition.org

J. Nutr. March 1, 2004 vol. 134 no. 3 489-492

© 2004 The American Society for Nutritional Sciences

Glutathione Metabolism and ItsImplications for Health1

Guoyao Wu2, Yun-Zhong Fang

*, Sheng Yang

†, Joanne R. Lupton, and

Nancy D. Turner

Author Affiliations

↵2To whom correspondence should be addressed. E-mail: [email protected].

Abstract

Glutathione (γ-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weightthiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesisof GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolicenzymes, γ-glutamylcysteine synthetase and GSH synthetase. Compelling evidence showsthat GSH synthesis is regulated primarily by γ-glutamylcysteine synthetase activity, cysteineavailability, and GSH feedback inhibition. Animal and human studies demonstrate thatadequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition,enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathioneplays important roles in antioxidant defense, nutrient metabolism, and regulation of cellularevents (including gene expression, DNA and protein synthesis, cell proliferation andapoptosis, signal transduction, cytokine production and immune response, and proteinglutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a keyrole in aging and the pathogenesis of many diseases (including kwashiorkor, seizure,Alzheimer’s disease, Parkinson’s disease, liver disease, cystic fibrosis, sickle cell anemia,HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritionalregulation of GSH metabolism is critical for the development of effective strategies toimprove health and to treat these diseases.

amino acids oxidative stress cysteine disease

The work with glutathione (γ-glutamyl-cysteinyl-glycine; GSH)3 has greatly advancedbiochemical and nutritional sciences over the past 125 y (1,2). Specifically, these studieshave led to the free radical theory of human diseases and to the advancement of nutritionaltherapies to improve GSH status under various pathological conditions (2,3). Remarkably,the past decade witnessed the discovery of novel roles for GSH in signal transduction,gene expression, apoptosis, protein glutathionylation, and nitric oxide (NO) metabolism(2,4). Most recently, studies of in vivo GSH turnover in humans were initiated to providemuch-needed information about quantitative aspects of GSH synthesis and catabolism inthe whole body and specific cell types (e.g., erythrocytes) (3,5–7). This article reviews therecent developments in GSH metabolism and its implications for health and disease.

Abundance of GSH in Cells and Plasma.

Glutathione is the predominant low-molecular-weight thiol (0.5–10 mmol/L) in animal cells.Most of the cellular GSH (85–90%) is present in the cytosol, with the remainder in manyorganelles (including the mitochondria, nuclear matrix, and peroxisomes) (8). With theexception of bile acid, which may contain up to 10 mmol/L GSH, extracellularconcentrations of GSH are relatively low (e.g., 2–20 µmol/L in plasma) (4,9). Because ofthe cysteine residue, GSH is readily oxidized nonenzymatically to glutathione disulfide(GSSG) by electrophilic substances (e.g., free radicals and reactive oxygen/nitrogenspecies). The GSSG efflux from cells contributes to a net loss of intracellular GSH. CellularGSH concentrations are reduced markedly in response to protein malnutrition, oxidativestress, and many pathological conditions (8,9). The GSH + 2GSSG concentration is usuallydenoted as total glutathione in cells, a significant amount of which (up to 15%) may bebound to protein (1). The [GSH]:[GSSG] ratio, which is often used as an indicator of thecellular redox state, is >10 under normal physiological conditions (9). GSH/GSSG is themajor redox couple that determines the antioxidative capacity of cells, but its value can beaffected by other redox couples, including NADPH/NADP+ and thioredoxinred/thioredoxinox(4).

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GSH Synthesis.

The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially bytwo cytosolic enzymes, γ-glutamylcysteine synthetase (GCS) and GSH synthetase (Fig. 1).This pathway occurs in virtually all cell types, with the liver being the major producer andexporter of GSH. In the GCS reaction, the γ-carboxyl group of glutamate reacts with theamino group of cysteine to form a peptidic γ-linkage, which protects GSH from hydrolysisby intracellular peptidases. Although γ-glutamyl-cysteine can be a substrate forγ-glutamylcyclotransferase, GSH synthesis is favored in animal cells because of the muchhigher affinity and activity of GSH synthetase (9).

FIGURE 1

Glutathione synthesis andutilization in animals. Enzymes thatcatalyze the indicated reactionsare: 1) γ-glutamyl transpeptidase,2) γ-glutamyl cyclotransferase, 3)5-oxoprolinase, 4) γ-glutamyl-cysteine synthetase, 5) glutathionesynthetase, 6) dipeptidase, 7)glutathione peroxidase, 8)glutathione reductase, 9)superoxide dismutase, 10) BCAAtransaminase (cytosolic and

mitochondrial), 11) glutaminase, 12) glutamate dehydrogenase, 13)glutamine:fructose-6-phosphate transaminase (cytosolic), 14) nitric oxidesynthase, 15) glutathione S-transferase, 16) NAD(P)H oxidase andmitochondrial respiratory complexes, 17) glycolysis, 18) glutathione-dependentthioldisulfide or thioltransferase or nonenzymatic reaction, 19) transsulfurationpathway, 20) deacylase, and 21) serine hydroxymethyltransferase.Abbreviations: AA, amino acids; BCKA, branched-chain α-ketoacids; GlcN-6-P,glucosamine-6-phosphate; GS-NO, glutathione-nitric oxide adduct; KG,α-ketoglutarate; LOO·, lipid peroxyl radical; LOOH, lipid hydroperoxide; NAC,N-acetylcysteine; OTC, L-2-oxothiazolidine-4-carboxylate; R·, radicals; R,nonradicals; R-5-P, ribulose-5-phosphate; X, electrophilic xenobiotics.

Mammalian GCS is a heterodimer consisting of a catalytically active heavy subunit (73kDa) and a light (regulatory) subunit (31 kDa) (8). The heavy subunit contains all substratebinding sites, whereas the light subunit modulates the affinity of the heavy subunit forsubstrates and inhibitors. The Km values of mammalian GCS for glutamate and cysteineare 1.7 and 0.15 mmol/L, respectively, which are similar to the intracellular concentrationsof glutamate (2–4 mmol/L) and cysteine (0.15–0.25 mmol/L) in rat liver (9). MammalianGSH synthetase is a homodimer (52 kDa/subunit) and is an allosteric enzyme withcooperative binding for γ-glutamyl substrate (10). The Km values of mammalian GSHsynthetase for ATP and glycine are ∼0.04 and 0.9 mmol/L, respectively, which are lowerthan intracellular concentrations of ATP (2–4 mmol/L) and glycine (1.5–2 mmol/L) in ratliver. Both subunits of rat GCS and GSH synthetase have been cloned and sequenced (9),which facilitates the study of molecular regulation of GSH synthesis. γ-Glutamylcysteinesynthetase is the rate-controlling enzyme in de novo synthesis of GSH (8).

Knowledge regarding in vivo GSH synthesis is limited, due in part to the complexcompartmentalization of substrates and their metabolism at both the organ and subcellularlevels. For example, the source of glutamate for GCS differs between the small intestineand kidney (e.g., diet vs. arterial blood). In addition, liver GSH synthesis occurspredominantly in perivenous hepatocytes and, to a lesser extent, in periportal cells (11).Thus, changes in plasma GSH levels may not necessarily reflect changes in GSH synthesisin specific cell types. However, recent studies involving stable isotopes (5–7) haveexpanded our understanding of GSH metabolism. In healthy adult humans, theendogenous disappearance rate (utilization rate) of GSH is 25 µmol/(kg · h) (6), whichaccounts for 65% of whole body cysteine flux [38.3 µmol/(kg · h)]. This finding supports theview that GSH acts as a major transport form of cysteine in the body. On the basis ofdietary cysteine intake [9 µmol/(kg · h)] in healthy adult humans (6), it is estimated thatmost of the cysteine used for endogenous GSH synthesis is derived from intracellularprotein degradation and/or endogenous synthesis. Interestingly, among extrahepatic cells,the erythrocyte has a relatively high turnover rate for GSH. For example, the whole-bloodfractional synthesis rate of GSH in healthy adult subjects is 65%/d (6), which means that allthe GSH is completely replaced in 1.5 d; this value is equivalent to 3 µmol/(kg · h). Thus,


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whole blood (mainly erythrocytes) may contribute up to 10% of whole-body GSH synthesisin humans (5,6).

Regulation of GSH Synthesis by GCS.

Oxidant stress, nitrosative stress, inflammatory cytokines, cancer, cancer chemotherapy,ionizing radiation, heat shock, inhibition of GCS activity, GSH depletion, GSH conjugation,prostaglandin A2, heavy metals, antioxidants, and insulin increase GCS transcription oractivity in a variety of cells (2,8). In contrast, dietary protein deficiency, dexamethasone,erythropoietin, tumor growth factor β, hyperglycemia, and GCS phosphorylation decreaseGCS transcription or activity. Nuclear factor κB mediates the upregulation of GCSexpression in response to oxidant stress, inflammatory cytokines, and buthioninesulfoximine-induced GSH depletion (2,8). S-nitrosation of GCS protein by NO donors (e.g.,S-nitroso-L-cysteine and S-nitroso-L-cysteinylglycine) reduces enzyme activity (8),suggesting a link between NO (a metabolite of L-arginine) and GSH metabolism. Indeed, anincrease in NO production by inducible NO synthase causes GCS inhibition and GSHdepletion in cytokine-activated macrophages and neurons (12). In this regard, glucosamine,taurine, n-3 PUFAs, phytoestrogens, polyphenols, carotenoids, and zinc, which inhibit theexpression of inducible NO synthase and NO production (13), may prevent or attenuateGSH depletion in cells. Conversely, high-fat diet, saturated long-chain fatty acids,low-density lipoproteins, linoleic acid, and iron, which enhance the expression of inducibleNO synthase and NO production (13), may exacerbate the loss of GSH from cells.

Regulation of GSH Synthesis by Amino Acids.

Cysteine is an essential amino acid in premature and newborn infants and in subjectsstressed by disease (14). As noted above, the intracellular pool of cysteine is relativelysmall, compared with the much larger and often metabolically active pool of GSH in cells(15). Recent studies provide convincing data to support the view that cysteine is generallythe limiting amino acid for GSH synthesis in humans, as in rats, pigs, and chickens(6,14,15). Thus, factors (e.g., insulin and growth factors) that stimulate cysteine (cystine)uptake by cells generally increase intracellular GSH concentrations (8). In addition,increasing the supply of cysteine or its precursors (e.g., cystine, N-acetyl-cysteine, andL-2-oxothiazolidine-4-carboxylate) via oral or intravenous administration enhances GSHsynthesis and prevents GSH deficiency in humans and animals under various nutritionaland pathological conditions (including protein malnutrition, adult respiratory distresssyndrome, HIV, and AIDS) (2). Because cysteine generated from methionine catabolism viathe transsulfuration pathway (primarily in hepatocytes) serves as a substrate for GCS,dietary methionine can replace cysteine to support GSH synthesis in vivo.

Cysteine is readily oxidized to cystine in oxygenated extracellular solutions. Thus, theplasma concentration of cysteine is low (10–25 µmol/L), compared with that of cystine(50–150 µmol/L). Cysteine and cystine are transported by distinct membrane carriers, andcells typically transport one more efficiently than the other (8). It is interesting that some celltypes (e.g., hepatocytes) have little or no capacity for direct transport of extracellularcystine. However, GSH that effluxes from the liver can reduce cystine to cysteine on theouter cell membrane, and the resulting cysteine is taken up by hepatocytes. Other celltypes (e.g., endothelial cells) can take up cystine and reduce it intracellularly to cysteine(Fig. 1); cellular reducing conditions normally favor the presence of cysteine in animal cells.

Extracellular and intracellularly generated glutamate can be used for GSH synthesis (16).Because dietary glutamate is almost completely utilized by the small intestine (16), plasmaglutamate is derived primarily from its de novo synthesis and protein degradation.Phosphate-dependent glutaminase, glutamate dehydrogenase, pyrroline-5-carboxylatedehydrogenase, BCAA transaminase, and glutamine:fructose-6-phosphate transaminasemay catalyze glutamate formation (Fig. 1), but the relative importance of these enzymeslikely varies among cells and tissues. Interestingly, rat erythrocytes do not take up orrelease glutamate (17), and glutamine and/or BCAAs may be the precursors of glutamatein these cells (Fig. 1). Indeed, glutamine is an effective precursor of the glutamate for GSHsynthesis in many cell types, including enterocytes, neural cells, liver cells, andlymphocytes (18). Thus, glutamine supplementation to total parenteral nutrition maintainstissue GSH levels and improves survival after reperfusion injury, ischemia, acetaminophentoxicity, chemotherapy, inflammatory stress, and bone marrow transplantation (19).

Glutamate plays a regulatory role in GSH synthesis through two mechanisms: 1) the uptakeof cystine, and 2) the prevention of GSH inhibition of GCS. Glutamate and cystine sharethe system Xc

− amino acid transporter (8). When extracellular glutamate concentrations arehigh, as in patients with advanced cancer, HIV infection, and spinal cord or brain injury aswell as in cell culture medium containing high levels of glutamate, cystine uptake iscompetitively inhibited by glutamate, resulting in reduced GSH synthesis (20). GSH is a


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nonallosteric feedback inhibitor of GCS, but the binding of GSH to the enzyme competeswith glutamate (9). When intracellular glutamate concentrations are unusually high, as incanine erythrocytes, GSH synthesis is enhanced and its concentration is particularly high(9).

Glycine availability may be reduced in response to protein malnutrition, sepsis, andinflammatory stimuli (21,22). When hepatic glycine oxidation is enhanced in response tohigh levels of glucagon or diabetes (23), this amino acid may become a limiting factor forGSH synthesis. In vivo studies show that glycine availability limits erythrocyte GSHsynthesis in burned patients (7) and in children recovering from severe malnutrition (21). Itis important to note that dietary glycine supplementation enhances the hepatic GSHconcentration in protein-deficient rats challenged with TNF-α (22).

The evidence indicates that the dietary amino acid balance has an important effect onprotein nutrition and therefore on GSH homeostasis (8). In particular, the adequateprovision of sulfur-containing amino acids as well as glutamate (glutamine or BCAAs) andglycine (or serine) is critical for the maximization of GSH synthesis. Thus, in theerythrocytes of children with edematous protein-energy malnutrition and piglets with proteindeficiency, GSH synthesis is impaired, leading to GSH deficiency (3). An increase in urinaryexcretion of 5-oxoproline, an intermediate of the γ-glutamyl cycle (Fig. 1), is a usefulindicator of reduced availability of cysteine and/or glycine for GSH synthesis in vivo (7,21)

Interorgan GSH Transport.

Glutathione can be transported out of cells via a carrier-dependent facilitated mechanism(2). Plasma GSH originates primarily from the liver, but some of the dietary and intestinallyderived GSH can enter the portal venous plasma (8). Glutathione molecules leave the livereither intact or as γ-Glu-(Cys)2 owing to γ-glutamyl transpeptidase activity on the outerplasma membrane (Fig. 1). The extreme concentration gradient across the plasmamembrane makes the transport of extracellular GSH or GSSG into cells thermodynamicallyunfavorable. However, γ-Glu-(Cys)2 is readily taken up by extrahepatic cells for GSHsynthesis. The kidney, lung, and intestine are major consumers of the liver-derived GSH(8). The interorgan metabolism of GSH functions to transport cysteine in a nontoxic formbetween tissues, and also helps to maintain intracellular GSH concentrations and redoxstate (8).

Roles of GSH.

Glutathione participates in many cellular reactions. First, GSH effectively scavenges freeradicals and other reactive oxygen species (e.g., hydroxyl radical, lipid peroxyl radical,peroxynitrite, and H2O2) directly, and indirectly through enzymatic reactions (24). In suchreactions, GSH is oxidized to form GSSG, which is then reduced to GSH by the NADPH-dependent glutathione reductase (Fig. 1). In addition, glutathione peroxidase (a selenium-containing enzyme) catalyzes the GSH-dependent reduction of H2O2 and other peroxides(25).

Second, GSH reacts with various electrophiles, physiological metabolites (e.g., estrogen,melanins, prostaglandins, and leukotrienes), and xenobiotics (e.g., bromobenzene andacetaminophen) to form mercapturates (24). These reactions are initiated by glutathione-S-transferase (a family of Phase II detoxification enzymes).

Third, GSH conjugates with NO to form an S-nitroso-glutathione adduct, which is cleavedby the thioredoxin system to release GSH and NO (24). Recent evidence suggests that thetargeting of endogenous NO is mediated by intracellular GSH (26). In addition, both NOand GSH are necessary for the hepatic action of insulin-sensitizing agents (27), indicatingtheir critical role in regulating lipid, glucose, and amino acid utilization.

Fourth, GSH serves as a substrate for formaldehyde dehydrogenase, which convertsformaldehyde and GSH to S-formyl-glutathione (2). The removal of formaldehyde (acarcinogen) is of physiological importance, because it is produced from the metabolism ofmethionine, choline, methanol (alcohol dehydrogenase), sarcosine (sarcosine oxidase),and xenobiotics (via the cytochrome P450-dependent monooxygenase system of theendoplasmic reticulum).

Fifth, GSH is required for the conversion of prostaglandin H2 (a metabolite of arachidonicacid) into prostaglandins D2 and E2 by endoperoxide isomerase (8).

Sixth, GSH is involved in the glyoxalase system, which converts methylglyoxal to D-lactate,a pathway active in microorganisms. Finally, glutathionylation of proteins (e.g., thioredoxin,ubiquitin-conjugating enzyme, and cytochrome c oxidase) plays an important role in cellphysiology (2).


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Thus, GSH serves vital functions in animals (Table 1). Adequate GSH concentrations arenecessary for the proliferation of cells, including lymphocytes and intestinal epithelial cells(28). Glutathione also plays an important role in spermatogenesis and sperm maturation(1). In addition, GSH is essential for the activation of T-lymphocytes andpolymorphonuclear leukocytes as well as for cytokine production, and therefore formounting successful immune responses when the host is immunologically challenged (2).Further, both in vitro and in vivo evidence show that GSH inhibits infection by the influenzavirus (29). It is important to note that shifting the GSH/GSSG redox toward the oxidizingstate activates several signaling pathways (including protein kinase B, proteinphosphatases 1 and 2A, calcineurin, nuclear factor κB, c-Jun N-terminal kinase, apoptosissignal-regulated kinase 1, and mitogen-activated protein kinase), thereby reducing cellproliferation and increasing apoptosis (30). Thus, oxidative stress (a deleterious imbalancebetween the production and removal of reactive oxygen/nitrogen species) plays a key rolein the pathogenesis of many diseases, including cancer, inflammation, kwashiorkor(predominantly protein deficiency), seizure, Alzheimer’s disease, Parkinson’s disease,sickle cell anemia, liver disease, cystic fibrosis, HIV, AIDS, infection, heart attack, stroke,and diabetes (2,31).

TABLE 1

Roles of glutathione in animals

Concluding Remarks and Perspectives.

GSH displays remarkable metabolic and regulatory versatility. GSH/GSSG is the mostimportant redox couple and plays crucial roles in antioxidant defense, nutrient metabolism,and the regulation of pathways essential for whole body homeostasis. Glutathionedeficiency contributes to oxidative stress, and, therefore, may play a key role in aging andthe pathogenesis of many diseases. This presents an emerging challenge to nutritionalresearch. Protein (or amino acid) deficiency remains a significant nutritional problem in theworld, owing to inadequate nutritional supply, nausea and vomiting, premature birth, HIV,AIDS, cancer, cancer chemotherapy, alcoholism, burns, and chronic digestive diseases.Thus, new knowledge regarding the efficient utilization of dietary protein or the precursorsfor GSH synthesis and its nutritional status is critical for the development of effectivetherapeutic strategies to prevent and treat a wide array of human diseases, includingcardiovascular complications, cancer, and severe acute respiratory syndrome.

Acknowledgments

We thank Tony Haynes for assistance in manuscript preparation.

Footnotes

↵1 Supported by grants from the American Heart Association (0255878Y), theNational Institutes of Health (R01CA61750), the National Space Biomedical ResearchInstitute (00202), and the National Institute of Environmental Health Sciences(P30-ES09106).

↵3 Abbreviations used: GCS, γ-glutamylcysteine synthetase; GSH, glutathione;GSSG, glutathione disulfide.

Manuscript received: December 5, 2003.Initial review completed: December 16, 2003.Revision accepted: December 18, 2003.

LITERATURE CITED

1. Sies, H. (1999) Glutathione and its cellular functions. Free Radic. Biol. Med.27:916-921. CrossRef Medline

2. Townsend, D. M., Tew, K. D. & Tapiero, H. (2003) The importance of glutathione inhuman disease. Biomed. Pharmacother. 57:145-155. CrossRef Medline

3. Badaloo, A., Reid, M., Forrester, T., Heird, W. C. & Jahoor, F. (2002) Cysteinesupplementation improves the erythrocyte glutathione synthesis rate in children withsevere edematous malnutrition. Am. J. Clin. Nutr. 76:646-652. Abstract/FREE Full Text

4. Jones, D. P. (2002) Redox potential of GSH/GSSG couple: assay and biologicalsignificance. Methods Enzymol. 348:93-112. Medline

5. Reid, M., Badaloo, A., Forrester, T., Morlese, J. F., Frazer, M., Heird, W. C. & Jahoor, F.(2000) In vivo rates of erythrocyte glutathione synthesis in children with severe protein-


5 of 14 5/27/12 1:38 AM

energy malnutrition. Am. J. Physiol. 278:E405-E412.

6. Lyons, J., Rauh-Pfeiffer, A., Yu, Y. M., Lu, X. M., Zurakowski, D., Tompkins, R. G.,Ajami, A. M., Young, V. R. & Castillo, L. (2000) Blood glutathione synthesis rates in healthyadults receiving a sulfur amino acid-free diet. Proc. Natl. Acad. Sci. U.S.A. 97:5071-5076.

Abstract/FREE Full Text

7. Yu, Y. M., Ryan, C. M., Fei, Z. W., Lu, X. M., Castillo, L., Schultz, J. T., Tompkins, R. G.& Young, V. R. (2002) Plasma L-5-oxoproline kinetics and whole blood glutathionesynthesis rates in severely burned adult humans. Am. J. Physiol. 282:E247-E258.

8. Lu, S. C. (2000) Regulation of glutathione synthesis. Curr. Top. Cell Regul. 36:95-116.Medline

9. Griffith, O. W. (1999) Biologic and pharmacologic regulation of mammalian glutathionesynthesis. Free Radic. Biol. Med. 27:922-935. CrossRef Medline

10. Njalsson, R., Norgren, S., Larsson, A., Huang, C. S., Anderson, M. E. & Luo, J. L.(2001) Cooperative binding of γ-glutamyl substrate to human glutathione synthetase.Biochem. Biophys. Res. Commun. 289:80-84. CrossRef Medline

11. Bella, D. L., Hirschberger, L. L., Kwon, Y. H. & Stipanuk, M. H. (2002) Cysteinemetabolism in periportal and perivenous hepatocytes: perivenous cells have greatercapacity for glutathione production and taurine synthesis but not for cysteine catabolism.Amino Acids 23:453-458. Medline

12. Canals, S., Casarejos, M. J., de Bernardo, S., Rodriguez-Martin, E. & Mena, M. A.(2003) Nitric oxide triggers the toxicity due to glutathione depletion in midbrain culturesthrough 12-lipoxygenase. J. Biol. Chem. 278:21542-21549. Abstract/FREE Full Text

13. Wu, G. & Meininger, C. J. (2002) Regulation of nitric oxide synthesis by dietary factors.22:61-86.

14. Jahoor, F., Jackson, A., Gazzard, B., Philips, G., Sharpstone, D., Frazer, M. E. &Heird, W. (1999) Erythrocyte glutathione deficiency in symptom-free HIV infection isassociated with decreased synthesis rate. Am. J. Physiol. 276:E205-E211.

15. Chung, T. K., Funk, M. A. & Baker, D. H. (1990) L-2-oxothiazolidine-4-carboxylate as acysteine precursor—efficacy for growth and hepatic glutathione synthesis in chicks andrats. J. Nutr. 120:158-165.

16. Reeds, P. J., Burrin, D. G., Stoll, B., Jahoor, F., Wykes, L., Henry, J. & Frazer, M. E.(1997) Enteral glutamate is the preferential source for mucosal glutathione synthesis infed piglets. Am. J. Physiol. 273:E408-E415.

17. Watford, M. (2002) Net interorgan transport of L-glutamate occurs via the plasma, notvia erythrocytes. J. Nutr. 132:952-956. Abstract/FREE Full Text

18. Johnson, A. T., Kaufmann, Y. C., Luo, S., Todorova, V. & Klimberg, V. S. (2003) Effectof glutamine on glutathione, IGF-1, and TGF-β1. J. Surg. Res. 111:222-228. Medline

19. Oehler, R. & Roth, E. (2003) Regulative capacity of glutamine. Curr. Opin. Clin. Nutr.Metab. Care 6:277-282. CrossRef Medline

20. Tapiero, H., Mathe, G., Couvreur, P. & Tew, K. D. (2002) Glutamine and glutamate.Biomed. Pharmacother. 56:446-457. CrossRef Medline

21. Persaud, C., Forrester, T. & Jackson, A. (1996) Urinary excretion of 5-L-oxoproline(pyroglutamic acid) is increased during recovery from severe childhood malnutrition andresponds to supplemental glycine. J. Nutr. 126:2823-2830.

22. Grimble, R. F., Jackson, A. A., Persaud, C., Wride, M. J., Delers, F. & Engler, R. (1992)Cysteine and glycine supplementation modulate the metabolic response to tumor necrosisfactor-α in rats fed a low protein diet. J. Nutr. 122:2066-2073.

23. Mabrouk, G. M., Jois, M. & Brosnan, J. T. (1998) Cell signaling and the hormonalstimulation of the hepatic glycine cleavage enzyme system by glucagon. Biochem. J.330:759-763.

24. Fang, Y. Z., Yang, S. & Wu, G. (2002) Free radicals, antioxidants, and nutrition.Nutrition 18:872-879. CrossRef Medline

25. Lei, X. G. (2002) In vivo antioxidant role of glutathione peroxidase: evidence fromknockout mice. Methods Enzymol. 347:213-225. Medline

26. André, M. & Felley-Bosco, E. (2003) Heme oxygenase-1 induction by endogenousnitric oxide: influence of intracellular glutathione. FEBS Lett. 546:223-227. CrossRef

Medline

27. Guarino, M. P., Afonso, R. A., Raimundo, N., Raposo, J. F. & Macedo, M. P. (2003)Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substanceaction. Am. J. Physiol. 284:G588-G594.

28. Aw, T. Y. (2003) Cellular redox: a modulator of intestinal epithelial cell proliferation.News Physiol. Sci. 18:201-204. Abstract/FREE Full Text

29. Cai, J., Chen, Y., Seth, S., Furukawa, S., Compans, R. W. & Jones, D. P. (2003)Inhibition of influenza infection by glutathione. Free Radic. Biol. Med. 34:928-936.

CrossRef Medline

30. Sen, C. K. (2000) Cellular thiols and redox-regulated signal transduction. Curr. Top.Cell Regul. 36:1-30. Medline


6 of 14 5/27/12 1:38 AM

31. Turrens, J. F. (2003) Mitochondrial formation of reactive oxygen species. J. Physiol.552:335-344. Abstract/FREE Full Text

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Vitamin B-6 restriction tends to reduce the red blood cell glutathionesynthesis rate without affecting red blood cell or plasma glutathioneconcentrations in healthy men and women


Serum Folate and DDT Isomers and Metabolites Are Inversely Associatedin Chinese Women: A Cross-Sectional Analysis

J. Am. Coll. Nutr. 2009 28: 380-387


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Abstract Full Text Full Text (PDF)

Glutathione homeostasis in ventricular myocytes from rat hearts withchronic myocardial infarction

Exp Physiol 2009 94: 815-824Abstract Full Text Full Text (PDF)

Hypothalamic Reactive Oxygen Species Are Required for Insulin-InducedFood Intake Inhibition: An NADPH Oxidase-Dependent Mechanism


Curcumin Eliminates Leptin's Effects on Hepatic Stellate Cell Activation viaInterrupting Leptin Signaling

Endocrinology 2009 150: 3011-3020Abstract Full Text Full Text (PDF)

Sulfur amino acid deficiency upregulates intestinal methionine cycleactivity and suppresses epithelial growth in neonatal pigs

Am. J. Physiol. Endocrinol. Metab. 2009 296: E1239-E1250Abstract Full Text Full Text (PDF)

Dietary L-Arginine Supplementation Reduces White Fat Gain andEnhances Skeletal Muscle and Brown Fat Masses in Diet-Induced ObeseRats

J. Nutr. 2009 139: 230-237Abstract Full Text Full Text (PDF)

Effects of rumen-protected methionine supplementation and bacteriallipopolysaccharide infusion on nitrogen metabolism and hormonalresponses of growing beef steers


Role of Enzymatic N-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Drug Metab. Dispos. 2009 37: 97-105Abstract Full Text Full Text (PDF)

Select Nutrients in the Ovine Uterine Lumen. I. Amino Acids, Glucose, andIons in Uterine Lumenal Flushings of Cyclic and Pregnant Ewes

Biol. Reprod. 2009 80: 86-93Abstract Full Text Full Text (PDF)

Probable Trimethoprim/Sulfamethoxazole-Induced Higher-Level GaitDisorder and Nocturnal Delirium in an Elderly Man

The Annals of Pharmacotherapy 2009 43: 129-133Abstract Full Text Full Text (PDF)

Glutathione Depletion and Disruption of Intracellular Ionic HomeostasisRegulate Lymphoid Cell Apoptosis


Analysis of chloroethane toxicity and carcinogenicity including acomparison with bromoethane

Toxicol Ind Health 2008 24: 655-675Abstract Full Text (PDF)

One-Carbon Metabolism Biomarkers and Risk of Colon and Rectal CancersCancer Epidemiol. Biomarkers Prev. 2008 17: 3233-3240


Combined enteral infusion of glutamine, carbohydrates, and antioxidants


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modulates gut protein metabolism in humansAm J Clin Nutr 2008 88: 1284-1290


Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact onMuscle Force Production

Physiol. Rev. 2008 88: 1243-1276Abstract Full Text Full Text (PDF)

Redox regulation of mitochondrial sulfide oxidation in the lugworm,Arenicola marina


Dietary Arginine Supplementation during Early Pregnancy EnhancesEmbryonic Survival in Rats


Regulation of the susceptibility to oxidative stress by cysteine availabilityin pancreatic {beta}-cells


Dietary Arginine Supplementation Affects Microvascular Development inthe Small Intestine of Early-Weaned Pigs


Glutathione peroxidase 1 Pro198Leu variant contributes to the metabolicsyndrome in men in a large Japanese cohort


Gene Expression Is Altered in Piglet Small Intestine by Weaning andDietary Glutamine Supplementation


Muscle Disuse: Adaptation of Antioxidant Systems Is Age DependentJ Gerontol A Biol Sci Med Sci 2008 63: 461-466


Baggs ewes adapt to maternal undernutrition and maintain conceptusgrowth by maintaining fetal plasma concentrations of amino acids


Elevated Gamma-Glutamyltransferase Activity and Perturbed Thiol ProfileAre Associated With Features of Metabolic Syndrome

Arterioscler. Thromb. Vasc. Bio. 2008 28: 587-593Abstract Full Text Full Text (PDF)

Curcumin Protects the Rat Liver from CCl4-Caused Injury andFibrogenesis by Attenuating Oxidative Stress and SuppressingInflammation

Mol. Pharmacol. 2008 73: 399-409Abstract Full Text Full Text (PDF)

Intrauterine Growth Restriction Affects the Proteomes of the SmallIntestine, Liver, and Skeletal Muscle in Newborn Pigs



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Erythrocyte glutamine depletion, altered redox environment, andpulmonary hypertension in sickle cell disease

Blood 2008 111: 402-410Abstract Full Text Full Text (PDF)

Iron Regulates L-Cystine Uptake and Glutathione Levels in Lens Epithelialand Retinal Pigment Epithelial Cells by Its Effect on Cytosolic Aconitase

IOVS 2008 49: 310-319Abstract Full Text Full Text (PDF)

Relationship of Dimethylglycine, Choline, and Betaine with Oxoproline inPlasma of Pregnant Women and Their Newborn Infants


Cystine-Glutamate Transporter SLC7A11 Mediates Resistance toGeldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin

Mol. Pharmacol. 2007 72: 1637-1646Abstract Full Text Full Text (PDF)

Influence of endophyte consumption and heat stress on intravaginaltemperatures, plasma lipid oxidation, blood selenium, and glutathioneredox of mononuclear cells in heifers grazing tall fescue


Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of AcuteSeizures in Adult Rats

J. Neurosci. 2007 27: 12007-12011Abstract Full Text Full Text (PDF)

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid CellsIndependent of Reactive Oxygen Species Formation


Hepatoprotective role of captopril on paraquat induced hepatotoxicityHum Exp Toxicol 2007 26: 789-794

Abstract Full Text (PDF)

Complex Signatures of Selection and Gene Conversion in the DuplicatedGlobin Genes of House Mice

Genetics 2007 177: 481-500Abstract Full Text Full Text (PDF)

Upregulation of {gamma}-glutamate-cysteine ligase as part of thelong-term adaptation process to iron accumulation in neuronal SH-SY5Ycells


Vitamin C Is an Essential Antioxidant That Enhances Survival ofOxidatively Stressed Human Vascular Endothelial Cells in the Presence ofa Vast Molar Excess of Glutathione


The Poor Digestibility of Rapeseed Protein Is Balanced by Its Very HighMetabolic Utilization in Humans


Choline-related supplements improve abnormal plasma methionine-homocysteine metabolites and glutathione status in children with cystic


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fibrosisAm J Clin Nutr 2007 85: 702-708


Genetic Variation in Mouse Beta Globin Cysteine Content ModifiesGlutathione Metabolism: Implications for the Use of Mouse Models

Exp Biol Med 2007 232: 437-444Abstract Full Text Full Text (PDF)

Antenatal antioxidant prevents adult hypertension, vascular dysfunction,and microvascular rarefaction associated with in utero exposure to alow-protein diet

Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007 292: R1236-R1245Abstract Full Text Full Text (PDF)

The Alternative Pathway of Glutathione Degradation Is Mediated by a NovelProtein Complex Involving Three New Genes in Saccharomyces cerevisiae

Genetics 2007 175: 1137-1151Abstract Full Text Full Text (PDF)

Gene Expression Analysis Offers Unique Advantages to Histopathology inLiver Biopsy Evaluations

Toxicol Pathol 2007 35: 276-283Abstract Full Text Full Text (PDF)

Local Glutathione Redox Status Does Not Regulate Ileal Mucosal Growthafter Massive Small Bowel Resection in Rats


Role for Mitochondrial Reactive Oxygen Species in Brain Lipid Sensing:Redox Regulation of Food Intake


Modular Protein Supplements and Their Application to Long-Term CareNutr Clin Pract 2006 21: 485-504


Genetic and Cellular Toxicology of Dental Resin MonomersJDR 2006 85: 870-877


BOARD-INVITED REVIEW: Intrauterine growth retardation: Implications forthe animal sciences


The Global Regulator Spx Functions in the Control of OrganosulfurMetabolism in Bacillus subtilis

J. Bacteriol. 2006 188: 5741-5751Abstract Full Text Full Text (PDF)

Evidence of Choline Depletion and Reduced Betaine and Dimethylglycinewith Increased Homocysteine in Plasma of Children with Cystic Fibrosis


Proteomics and Its Role in Nutrition ResearchJ. Nutr. 2006 136: 1759-1762


Differential Metabolomics Reveals Ophthalmic Acid as an Oxidative Stress


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Biomarker Indicating Hepatic Glutathione ConsumptionJ. Biol. Chem. 2006 281: 16768-16776


Opposing Roles for ERK1/2 in Neuronal Oxidative Toxicity: DISTINCTMECHANISMS OF ERK1/2 ACTION AT EARLY VERSUS LATE PHASES OFOXIDATIVE STRESS


Curcumin suppresses the expression of extracellular matrix genes inactivated hepatic stellate cells by inhibiting gene expression of connectivetissue growth factor

Am. J. Physiol. Gastrointest. Liver Physiol. 2006 290: G883-G893Abstract Full Text Full Text (PDF)

Glutathione depletion by buthionine sulfoximine induces DNA deletions inmice

Carcinogenesis 2006 27: 240-244Abstract Full Text Full Text (PDF)

Plasma Glutathione and Cystathionine Concentrations Are Elevated butCysteine Flux Is Unchanged by Dietary Vitamin B-6 Restriction in YoungMen and Women


Oxidative Stress and Pulmonary Function in the General PopulationAm J Epidemiol 2005 162: 1137-1145


Effects of Four Oxidants, Menadione, 1-Chloro-2,4-Dinitrobenzene,Hydrogen Peroxide and Cumene Hydroperoxide, on Fission YeastSchizosaccharmoyces pombe

J Biochem 2005 138: 797-804Abstract Full Text Full Text (PDF)

2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) DirectlyTargets Mitochondrial Glutathione to Induce Apoptosis in PancreaticCancer


Two major branches of anti-cadmium defense in the mouse:MTF-1/metallothioneins and glutathione

Nucleic Acids Res 2005 33: 5715-5727Abstract Full Text Full Text (PDF)

Cystine-Glutamate Transporter SLC7A11 in Cancer Chemosensitivity andChemoresistance

Cancer Res. 2005 65: 7446-7454Abstract Full Text Full Text (PDF)

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain TumorsJ. Neurosci. 2005 25: 7101-7110


L-Folic Acid Supplementation in Healthy Postmenopausal Women: Effecton Homocysteine and Glycolipid Metabolism

J. Clin. Endocrinol. Metab. 2005 90: 4622-4629Abstract Full Text Full Text (PDF)

Steatohepatitis develops rapidly in transgenic mice overexpressingAbcb11 and fed a methionine-choline-deficient diet


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Am. J. Physiol. Gastrointest. Liver Physiol. 2005 288: G1321-G1327Abstract Full Text Full Text (PDF)

Nutritional, Dietary and Postprandial Oxidative StressJ. Nutr. 2005 135: 969-972


Apoptotic killing of B-chronic lymphocytic leukemia tumor cells by allicingenerated in situ using a rituximab-alliinase conjugate

Molecular Cancer Therapeutics 2005 4: 325-332Abstract Full Text Full Text (PDF)

Metabolic biomarkers of increased oxidative stress and impairedmethylation capacity in children with autism



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Glutathione Metabolism and Its Implications for Health