Glutathione Metabolism and Its Implications for Health

http://jn.nutrition.org/content/134/3/489.full

The Journal of Nutrition

jn.nutrition.org J. Nutr. March 1, 2004 vol. 134 no. 3 489-492 2004 The American Society for Nutritional Sciences

Glutathione Metabolism and Its Implications for Health1

Guoyao Wu , Yun-Zhong Fang , Sheng Yang , Joanne R. Lupton, and Nancy D. Turner
+

Author Affiliations
2

To whom correspondence should be addressed. E-mail: g-wu@tamu.edu.

Abstract
Glutathione (-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, -glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by -glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimers disease, Parkinsons disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.
amino acids oxidative stress cysteine disease

The work with glutathione (-glutamyl-cysteinyl-glycine; GSH) has greatly advanced biochemical and nutritional sciences over the past 125 y (1,2). Specifically, these studies have led to the free radical theory of human diseases and to the advancement of nutritional therapies 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 provide much-needed information about quantitative aspects of GSH synthesis and catabolism in the whole body and specific cell types (e.g., erythrocytes) (3,57). This article reviews the recent 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 (0.510 mmol/L) in animal cells. Most of the cellular GSH (8590%) is present in the cytosol, with the remainder in many organelles (including the mitochondria, nuclear matrix, and peroxisomes) (8). With the exception of bile acid, which may contain up to 10 mmol/L GSH, extracellular concentrations of GSH are relatively low (e.g., 220 mol/L in plasma) (4,9). Because of the cysteine residue, GSH is readily oxidized nonenzymatically to glutathione disulfide (GSSG) by electrophilic substances (e.g., free radicals and reactive oxygen/nitrogen species). The GSSG efflux from cells contributes to a net loss of intracellular GSH. Cellular GSH concentrations are reduced markedly in response to protein malnutrition, oxidative stress, and many pathological conditions (8,9). The GSH + 2GSSG concentration is usually denoted as total glutathione in cells, a significant amount of which (up to 15%) may be bound to protein (1). The [GSH]:[GSSG] ratio, which is often used as an indicator of the cellular redox state, is >10 under normal physiological conditions (9). GSH/GSSG is the major redox couple that determines the antioxidative capacity of cells, but its value can be + affected by other redox couples, including NADPH/NADP and thioredoxin /thioredoxin red ox (4).

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

FIGURE 1 Glutathione synthesis and utilization in animals. Enzymes that catalyze the indicated reactions are: 1) -glutamyl transpeptidase, 2) -glutamyl cyclotransferase, 3) 5-oxoprolinase, 4) -glutamylcysteine synthetase, 5) glutathione
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synthetase, 6) dipeptidase, 7) glutathione peroxidase, 8) glutathione reductase, 9)

superoxide dismutase, 10) BCAA transaminase (cytosolic and mitochondrial), 11) glutaminase, 12) glutamate dehydrogenase, 13) glutamine:fructose-6-phosphate transaminase (cytosolic), 14) nitric oxide synthase, 15) glutathione S-transferase, 16) NAD(P)H oxidase and mitochondrial respiratory complexes, 17) glycolysis, 18) glutathione-dependent thioldisulfide or thioltransferase or nonenzymatic reaction, 19) transsulfuration pathway, 20) deacylase, and 21) serine hydroxymethyltransferase. Abbreviations: AA, amino acids; BCKA, branched-chain -ketoacids; GlcN-6-P, glucosamine-6-phosphate; GS-NO, glutathione-nitric oxide adduct; KG, -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 (73 kDa) and a light (regulatory) subunit (31 kDa) (8). The heavy subunit contains all substrate binding sites, whereas the light subunit modulates the affinity of the heavy subunit for substrates and inhibitors. The K values of mammalian GCS for glutamate and cysteine m are 1.7 and 0.15 mmol/L, respectively, which are similar to the intracellular concentrations of glutamate (24 mmol/L) and cysteine (0.150.25 mmol/L) in rat liver (9). Mammalian GSH synthetase is a homodimer (52 kDa/subunit) and is an allosteric enzyme with cooperative binding for -glutamyl substrate (10). The K values of mammalian GSH m synthetase for ATP and glycine are 0.04 and 0.9 mmol/L, respectively, which are lower than intracellular concentrations of ATP (24 mmol/L) and glycine (1.52 mmol/L) in rat liver. Both subunits of rat GCS and GSH synthetase have been cloned and sequenced (9), which facilitates the study of molecular regulation of GSH synthesis. -Glutamylcysteine synthetase 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 complex compartmentalization of substrates and their metabolism at both the organ and subcellular levels. For example, the source of glutamate for GCS differs between the small intestine and kidney (e.g., diet vs. arterial blood). In addition, liver GSH synthesis occurs predominantly 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 synthesis in specific cell types. However, recent studies involving stable isotopes (57) have expanded our understanding of GSH metabolism. In healthy adult humans, the endogenous disappearance rate (utilization rate) of GSH is 25 mol/(kg h) (6), which accounts for 65% of whole body cysteine flux [38.3 mol/(kg h)]. This finding supports the view that GSH acts as a major transport form of cysteine in the body. On the basis of dietary cysteine intake [9 mol/(kg h)] in healthy adult humans (6), it is estimated that most of the cysteine used for endogenous GSH synthesis is derived from intracellular protein degradation and/or endogenous synthesis. Interestingly, among extrahepatic cells, the erythrocyte has a relatively high turnover rate for GSH. For example, the whole-blood fractional synthesis rate of GSH in healthy adult subjects is 65%/d (6), which means that all the GSH is completely replaced in 1.5 d; this value is equivalent to 3 mol/(kg h). Thus,

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whole blood (mainly erythrocytes) may contribute up to 10% of whole-body GSH synthesis in 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 A , heavy metals, antioxidants, and insulin increase GCS transcription or activity in a variety of cells (2,8). In contrast, dietary protein deficiency, dexamethasone, erythropoietin, tumor growth factor , hyperglycemia, and GCS phosphorylation decrease GCS transcription or activity. Nuclear factor B mediates the upregulation of GCS expression in response to oxidant stress, inflammatory cytokines, and buthionine sulfoximine-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, an increase in NO production by inducible NO synthase causes GCS inhibition and GSH depletion in cytokine-activated macrophages and neurons (12). In this regard, glucosamine, taurine, n-3 PUFAs, phytoestrogens, polyphenols, carotenoids, and zinc, which inhibit the expression of inducible NO synthase and NO production (13), may prevent or attenuate GSH depletion in cells. Conversely, high-fat diet, saturated long-chain fatty acids, low-density lipoproteins, linoleic acid, and iron, which enhance the expression of inducible NO synthase and NO production (13), may exacerbate the loss of GSH from cells.
2

Regulation of GSH Synthesis by Amino Acids.

Cysteine is an essential amino acid in premature and newborn infants and in subjects stressed by disease (14). As noted above, the intracellular pool of cysteine is relatively small, 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 generally the 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, and L-2-oxothiazolidine-4-carboxylate) via oral or intravenous administration enhances GSH synthesis and prevents GSH deficiency in humans and animals under various nutritional and pathological conditions (including protein malnutrition, adult respiratory distress syndrome, HIV, and AIDS) (2). Because cysteine generated from methionine catabolism via the 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, the plasma concentration of cysteine is low (1025 mol/L), compared with that of cystine (50150 mol/L). Cysteine and cystine are transported by distinct membrane carriers, and cells typically transport one more efficiently than the other (8). It is interesting that some cell types (e.g., hepatocytes) have little or no capacity for direct transport of extracellular cystine. However, GSH that effluxes from the liver can reduce cystine to cysteine on the outer cell membrane, and the resulting cysteine is taken up by hepatocytes. Other cell types (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), plasma glutamate is derived primarily from its de novo synthesis and protein degradation. Phosphate-dependent glutaminase, glutamate dehydrogenase, pyrroline-5-carboxylate dehydrogenase, BCAA transaminase, and glutamine:fructose-6-phosphate transaminase may catalyze glutamate formation (Fig. 1), but the relative importance of these enzymes likely varies among cells and tissues. Interestingly, rat erythrocytes do not take up or release glutamate (17), and glutamine and/or BCAAs may be the precursors of glutamate in these cells (Fig. 1). Indeed, glutamine is an effective precursor of the glutamate for GSH synthesis in many cell types, including enterocytes, neural cells, liver cells, and lymphocytes (18). Thus, glutamine supplementation to total parenteral nutrition maintains tissue GSH levels and improves survival after reperfusion injury, ischemia, acetaminophen toxicity, chemotherapy, inflammatory stress, and bone marrow transplantation (19). Glutamate plays a regulatory role in GSH synthesis through two mechanisms: 1) the uptake of cystine, and 2) the prevention of GSH inhibition of GCS. Glutamate and cystine share the system X amino acid transporter (8). When extracellular glutamate concentrations are high, as in patients with advanced cancer, HIV infection, and spinal cord or brain injury as well as in cell culture medium containing high levels of glutamate, cystine uptake is competitively inhibited by glutamate, resulting in reduced GSH synthesis (20). GSH is a
c

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nonallosteric feedback inhibitor of GCS, but the binding of GSH to the enzyme competes with glutamate (9). When intracellular glutamate concentrations are unusually high, as in canine erythrocytes, GSH synthesis is enhanced and its concentration is particularly high (9). Glycine availability may be reduced in response to protein malnutrition, sepsis, and inflammatory stimuli (21,22). When hepatic glycine oxidation is enhanced in response to high levels of glucagon or diabetes (23), this amino acid may become a limiting factor for GSH synthesis. In vivo studies show that glycine availability limits erythrocyte GSH synthesis in burned patients (7) and in children recovering from severe malnutrition (21). It is important to note that dietary glycine supplementation enhances the hepatic GSH concentration in protein-deficient rats challenged with TNF- (22). The evidence indicates that the dietary amino acid balance has an important effect on protein nutrition and therefore on GSH homeostasis (8). In particular, the adequate provision of sulfur-containing amino acids as well as glutamate (glutamine or BCAAs) and glycine (or serine) is critical for the maximization of GSH synthesis. Thus, in the erythrocytes of children with edematous protein-energy malnutrition and piglets with protein deficiency, GSH synthesis is impaired, leading to GSH deficiency (3). An increase in urinary excretion of 5-oxoproline, an intermediate of the -glutamyl cycle (Fig. 1), is a useful indicator 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 intestinally derived GSH can enter the portal venous plasma (8). Glutathione molecules leave the liver either intact or as -Glu-(Cys) owing to -glutamyl transpeptidase activity on the outer 2 plasma membrane (Fig. 1). The extreme concentration gradient across the plasma membrane makes the transport of extracellular GSH or GSSG into cells thermodynamically unfavorable. However, -Glu-(Cys) is readily taken up by extrahepatic cells for GSH 2 synthesis. 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 form between tissues, and also helps to maintain intracellular GSH concentrations and redox state (8).

Roles of GSH.
Glutathione participates in many cellular reactions. First, GSH effectively scavenges free radicals and other reactive oxygen species (e.g., hydroxyl radical, lipid peroxyl radical, peroxynitrite, and H O ) directly, and indirectly through enzymatic reactions (24). In such 2 2 reactions, GSH is oxidized to form GSSG, which is then reduced to GSH by the NADPHdependent glutathione reductase (Fig. 1). In addition, glutathione peroxidase (a seleniumcontaining enzyme) catalyzes the GSH-dependent reduction of H O and other peroxides 2 2 (25). Second, GSH reacts with various electrophiles, physiological metabolites (e.g., estrogen, melanins, prostaglandins, and leukotrienes), and xenobiotics (e.g., bromobenzene and acetaminophen) to form mercapturates (24). These reactions are initiated by glutathioneS-transferase (a family of Phase II detoxification enzymes). Third, GSH conjugates with NO to form an S-nitroso-glutathione adduct, which is cleaved by the thioredoxin system to release GSH and NO (24). Recent evidence suggests that the targeting of endogenous NO is mediated by intracellular GSH (26). In addition, both NO and GSH are necessary for the hepatic action of insulin-sensitizing agents (27), indicating their critical role in regulating lipid, glucose, and amino acid utilization. Fourth, GSH serves as a substrate for formaldehyde dehydrogenase, which converts formaldehyde and GSH to S-formyl-glutathione (2). The removal of formaldehyde (a carcinogen) is of physiological importance, because it is produced from the metabolism of methionine, choline, methanol (alcohol dehydrogenase), sarcosine (sarcosine oxidase), and xenobiotics (via the cytochrome P450-dependent monooxygenase system of the endoplasmic reticulum). Fifth, GSH is required for the conversion of prostaglandin H (a metabolite of arachidonic acid) into prostaglandins D and E by endoperoxide isomerase (8).
2 2 2

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 cell physiology (2).

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Thus, GSH serves vital functions in animals (Table 1). Adequate GSH concentrations are necessary 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 and polymorphonuclear leukocytes as well as for cytokine production, and therefore for mounting 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 influenza virus (29). It is important to note that shifting the GSH/GSSG redox toward the oxidizing state activates several signaling pathways (including protein kinase B, protein phosphatases 1 and 2A, calcineurin, nuclear factor B, c-Jun N-terminal kinase, apoptosis signal-regulated kinase 1, and mitogen-activated protein kinase), thereby reducing cell proliferation and increasing apoptosis (30). Thus, oxidative stress (a deleterious imbalance between the production and removal of reactive oxygen/nitrogen species) plays a key role in the pathogenesis of many diseases, including cancer, inflammation, kwashiorkor (predominantly protein deficiency), seizure, Alzheimers disease, Parkinsons disease, sickle cell anemia, liver disease, cystic fibrosis, HIV, AIDS, infection, heart attack, stroke, and diabetes (2,31).

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TABLE 1 Roles of glutathione in animals

Concluding Remarks and Perspectives.

GSH displays remarkable metabolic and regulatory versatility. GSH/GSSG is the most important redox couple and plays crucial roles in antioxidant defense, nutrient metabolism, and the regulation of pathways essential for whole body homeostasis. Glutathione deficiency contributes to oxidative stress, and, therefore, may play a key role in aging and the pathogenesis of many diseases. This presents an emerging challenge to nutritional research. Protein (or amino acid) deficiency remains a significant nutritional problem in the world, 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 precursors for GSH synthesis and its nutritional status is critical for the development of effective therapeutic strategies to prevent and treat a wide array of human diseases, including cardiovascular complications, cancer, and severe acute respiratory syndrome.

Acknowledgments
We thank Tony Haynes for assistance in manuscript preparation.

Footnotes
Supported by grants from the American Heart Association (0255878Y), the National Institutes of Health (R01CA61750), the National Space Biomedical Research Institute (00202), and the National Institute of Environmental Health Sciences (P30-ES09106). Abbreviations used: GCS, -glutamylcysteine synthetase; GSH, glutathione; GSSG, glutathione disulfide. Manuscript received: December 5, 2003. Initial review completed: December 16, 2003. Revision accepted: December 18, 2003.
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Vitamin B-6 restriction tends to reduce the red blood cell glutathione synthesis rate without affecting red blood cell or plasma glutathione concentrations in healthy men and women Am J Clin Nutr 2009 90: 336-343 Abstract Full Text Full Text (PDF)

Serum Folate and DDT Isomers and Metabolites Are Inversely Associated in Chinese Women: A Cross-Sectional Analysis J. Am. Coll. Nutr. 2009 28: 380-387

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Glutathione homeostasis in ventricular myocytes from rat hearts with chronic myocardial infarction Exp Physiol 2009 94: 815-824 Abstract Full Text Full Text (PDF)

Hypothalamic Reactive Oxygen Species Are Required for Insulin-Induced Food Intake Inhibition: An NADPH Oxidase-Dependent Mechanism Diabetes 2009 58: 1544-1549 Abstract Full Text Full Text (PDF)

Curcumin Eliminates Leptin's Effects on Hepatic Stellate Cell Activation via Interrupting Leptin Signaling Endocrinology 2009 150: 3011-3020 Abstract Full Text Full Text (PDF)

Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs Am. J. Physiol. Endocrinol. Metab. 2009 296: E1239-E1250 Abstract Full Text Full Text (PDF)

Dietary L-Arginine Supplementation Reduces White Fat Gain and Enhances Skeletal Muscle and Brown Fat Masses in Diet-Induced Obese Rats J. Nutr. 2009 139: 230-237 Abstract Full Text Full Text (PDF)

Effects of rumen-protected methionine supplementation and bacterial lipopolysaccharide infusion on nitrogen metabolism and hormonal responses of growing beef steers J ANIM SCI 2009 87: 681-692 Abstract Full Text Full Text (PDF)

Role of Enzymatic N-Hydroxylation and Reduction in Flutamide MetaboliteInduced Liver Toxicity Drug Metab. Dispos. 2009 37: 97-105 Abstract Full Text Full Text (PDF)

Select Nutrients in the Ovine Uterine Lumen. I. Amino Acids, Glucose, and Ions in Uterine Lumenal Flushings of Cyclic and Pregnant Ewes Biol. Reprod. 2009 80: 86-93 Abstract Full Text Full Text (PDF)

Probable Trimethoprim/Sulfamethoxazole-Induced Higher-Level Gait Disorder and Nocturnal Delirium in an Elderly Man The Annals of Pharmacotherapy 2009 43: 129-133 Abstract Full Text Full Text (PDF)

Glutathione Depletion and Disruption of Intracellular Ionic Homeostasis Regulate Lymphoid Cell Apoptosis J. Biol. Chem. 2008 283: 36071-36087 Abstract Full Text Full Text (PDF)

Analysis of chloroethane toxicity and carcinogenicity including a comparison with bromoethane Toxicol Ind Health 2008 24: 655-675 Abstract Full Text (PDF)

One-Carbon Metabolism Biomarkers and Risk of Colon and Rectal Cancers Cancer Epidemiol. Biomarkers Prev. 2008 17: 3233-3240 Abstract Full Text Full Text (PDF)

Combined enteral infusion of glutamine, carbohydrates, and antioxidants

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modulates gut protein metabolism in humans Am J Clin Nutr 2008 88: 1284-1290 Abstract Full Text Full Text (PDF)

Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production Physiol. Rev. 2008 88: 1243-1276 Abstract Full Text Full Text (PDF)

Redox regulation of mitochondrial sulfide oxidation in the lugworm, Arenicola marina J. Exp. Biol. 2008 211: 2617-2623 Abstract Full Text Full Text (PDF)

Dietary Arginine Supplementation during Early Pregnancy Enhances Embryonic Survival in Rats J. Nutr. 2008 138: 1421-1425 Abstract Full Text Full Text (PDF)

Regulation of the susceptibility to oxidative stress by cysteine availability in pancreatic {beta}-cells Am. J. Physiol. Cell Physiol. 2008 295: C468-C474 Abstract Full Text Full Text (PDF)

Dietary Arginine Supplementation Affects Microvascular Development in the Small Intestine of Early-Weaned Pigs J. Nutr. 2008 138: 1304-1309 Abstract Full Text Full Text (PDF)

Glutathione peroxidase 1 Pro198Leu variant contributes to the metabolic syndrome in men in a large Japanese cohort Am J Clin Nutr 2008 87: 1939-1944 Abstract Full Text Full Text (PDF)

Gene Expression Is Altered in Piglet Small Intestine by Weaning and Dietary Glutamine Supplementation J. Nutr. 2008 138: 1025-1032 Abstract Full Text Full Text (PDF)

Muscle Disuse: Adaptation of Antioxidant Systems Is Age Dependent J Gerontol A Biol Sci Med Sci 2008 63: 461-466 Abstract Full Text Full Text (PDF)

Baggs ewes adapt to maternal undernutrition and maintain conceptus growth by maintaining fetal plasma concentrations of amino acids J ANIM SCI 2008 86: 820-826 Abstract Full Text Full Text (PDF)

Elevated Gamma-Glutamyltransferase Activity and Perturbed Thiol Profile Are Associated With Features of Metabolic Syndrome Arterioscler. Thromb. Vasc. Bio. 2008 28: 587-593 Abstract Full Text Full Text (PDF)

Curcumin Protects the Rat Liver from CCl4-Caused Injury and Fibrogenesis by Attenuating Oxidative Stress and Suppressing Inflammation Mol. Pharmacol. 2008 73: 399-409 Abstract Full Text Full Text (PDF)

Intrauterine Growth Restriction Affects the Proteomes of the Small Intestine, Liver, and Skeletal Muscle in Newborn Pigs J. Nutr. 2008 138: 60-66 Abstract Full Text Full Text (PDF)

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Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease Blood 2008 111: 402-410 Abstract Full Text Full Text (PDF)

Iron Regulates L-Cystine Uptake and Glutathione Levels in Lens Epithelial and Retinal Pigment Epithelial Cells by Its Effect on Cytosolic Aconitase IOVS 2008 49: 310-319 Abstract Full Text Full Text (PDF)

Relationship of Dimethylglycine, Choline, and Betaine with Oxoproline in Plasma of Pregnant Women and Their Newborn Infants J. Nutr. 2007 137: 2641-2646 Abstract Full Text Full Text (PDF)

Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin Mol. Pharmacol. 2007 72: 1637-1646 Abstract Full Text Full Text (PDF)

Influence of endophyte consumption and heat stress on intravaginal temperatures, plasma lipid oxidation, blood selenium, and glutathione redox of mononuclear cells in heifers grazing tall fescue J ANIM SCI 2007 85: 2932-2940 Abstract Full Text Full Text (PDF)

Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats J. Neurosci. 2007 27: 12007-12011 Abstract Full Text Full Text (PDF)

Glutathione Depletion Is Necessary for Apoptosis in Lymphoid Cells Independent of Reactive Oxygen Species Formation J. Biol. Chem. 2007 282: 30452-30465 Abstract Full Text Full Text (PDF)

Hepatoprotective role of captopril on paraquat induced hepatotoxicity Hum Exp Toxicol 2007 26: 789-794 Abstract Full Text (PDF)

Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice Genetics 2007 177: 481-500 Abstract Full Text Full Text (PDF)

Upregulation of {gamma}-glutamate-cysteine ligase as part of the long-term adaptation process to iron accumulation in neuronal SH-SY5Y cells Am. J. Physiol. Cell Physiol. 2007 292: C2197-C2203 Abstract Full Text Full Text (PDF)

Vitamin C Is an Essential Antioxidant That Enhances Survival of Oxidatively Stressed Human Vascular Endothelial Cells in the Presence of a Vast Molar Excess of Glutathione J. Biol. Chem. 2007 282: 15506-15515 Abstract Full Text Full Text (PDF)

The Poor Digestibility of Rapeseed Protein Is Balanced by Its Very High Metabolic Utilization in Humans J. Nutr. 2007 137: 594-600 Abstract Full Text Full Text (PDF)

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

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fibrosis Am J Clin Nutr 2007 85: 702-708 Abstract Full Text Full Text (PDF)

Genetic Variation in Mouse Beta Globin Cysteine Content Modifies Glutathione Metabolism: Implications for the Use of Mouse Models Exp Biol Med 2007 232: 437-444 Abstract Full Text Full Text (PDF)

Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007 292: R1236-R1245 Abstract Full Text Full Text (PDF)

The Alternative Pathway of Glutathione Degradation Is Mediated by a Novel Protein Complex Involving Three New Genes in Saccharomyces cerevisiae Genetics 2007 175: 1137-1151 Abstract Full Text Full Text (PDF)

Gene Expression Analysis Offers Unique Advantages to Histopathology in Liver Biopsy Evaluations Toxicol Pathol 2007 35: 276-283 Abstract Full Text Full Text (PDF)

Local Glutathione Redox Status Does Not Regulate Ileal Mucosal Growth after Massive Small Bowel Resection in Rats J. Nutr. 2007 137: 320-325 Abstract Full Text Full Text (PDF)

Role for Mitochondrial Reactive Oxygen Species in Brain Lipid Sensing: Redox Regulation of Food Intake Diabetes 2007 56: 152-160 Abstract Full Text Full Text (PDF)

Modular Protein Supplements and Their Application to Long-Term Care Nutr Clin Pract 2006 21: 485-504 Abstract Full Text Full Text (PDF)

Genetic and Cellular Toxicology of Dental Resin Monomers JDR 2006 85: 870-877 Abstract Full Text Full Text (PDF)

BOARD-INVITED REVIEW: Intrauterine growth retardation: Implications for the animal sciences J ANIM SCI 2006 84: 2316-2337 Abstract Full Text Full Text (PDF)

The Global Regulator Spx Functions in the Control of Organosulfur Metabolism in Bacillus subtilis J. Bacteriol. 2006 188: 5741-5751 Abstract Full Text Full Text (PDF)

Evidence of Choline Depletion and Reduced Betaine and Dimethylglycine with Increased Homocysteine in Plasma of Children with Cystic Fibrosis J. Nutr. 2006 136: 2226-2231 Abstract Full Text Full Text (PDF)

Proteomics and Its Role in Nutrition Research J. Nutr. 2006 136: 1759-1762 Abstract Full Text Full Text (PDF)

Differential Metabolomics Reveals Ophthalmic Acid as an Oxidative Stress

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Biomarker Indicating Hepatic Glutathione Consumption J. Biol. Chem. 2006 281: 16768-16776 Abstract Full Text Full Text (PDF)

Opposing Roles for ERK1/2 in Neuronal Oxidative Toxicity: DISTINCT MECHANISMS OF ERK1/2 ACTION AT EARLY VERSUS LATE PHASES OF OXIDATIVE STRESS J. Biol. Chem. 2006 281: 16436-16442 Abstract Full Text Full Text (PDF)

Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor Am. J. Physiol. Gastrointest. Liver Physiol. 2006 290: G883-G893 Abstract Full Text Full Text (PDF)

Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice Carcinogenesis 2006 27: 240-244 Abstract Full Text Full Text (PDF)

Plasma Glutathione and Cystathionine Concentrations Are Elevated but Cysteine Flux Is Unchanged by Dietary Vitamin B-6 Restriction in Young Men and Women J. Nutr. 2006 136: 373-378 Abstract Full Text Full Text (PDF)

Oxidative Stress and Pulmonary Function in the General Population Am J Epidemiol 2005 162: 1137-1145 Abstract Full Text Full Text (PDF)

Effects of Four Oxidants, Menadione, 1-Chloro-2,4-Dinitrobenzene, Hydrogen Peroxide and Cumene Hydroperoxide, on Fission Yeast Schizosaccharmoyces pombe J Biochem 2005 138: 797-804 Abstract Full Text Full Text (PDF)

2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) Directly Targets Mitochondrial Glutathione to Induce Apoptosis in Pancreatic Cancer J. Biol. Chem. 2005 280: 36273-36282 Abstract Full Text Full Text (PDF)

Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione Nucleic Acids Res 2005 33: 5715-5727 Abstract Full Text Full Text (PDF)

Cystine-Glutamate Transporter SLC7A11 in Cancer Chemosensitivity and Chemoresistance Cancer Res. 2005 65: 7446-7454 Abstract Full Text Full Text (PDF)

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors J. Neurosci. 2005 25: 7101-7110 Abstract Full Text Full Text (PDF)

L-Folic Acid Supplementation in Healthy Postmenopausal Women: Effect on Homocysteine and Glycolipid Metabolism J. Clin. Endocrinol. Metab. 2005 90: 4622-4629 Abstract Full Text Full Text (PDF)

Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet

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Am. J. Physiol. Gastrointest. Liver Physiol. 2005 288: G1321-G1327 Abstract Full Text Full Text (PDF)

Nutritional, Dietary and Postprandial Oxidative Stress J. Nutr. 2005 135: 969-972 Abstract Full Text Full Text (PDF)

Apoptotic killing of B-chronic lymphocytic leukemia tumor cells by allicin generated in situ using a rituximab-alliinase conjugate Molecular Cancer Therapeutics 2005 4: 325-332 Abstract Full Text Full Text (PDF)

Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism Am J Clin Nutr 2004 80: 1611-1617 Abstract Full Text Full Text (PDF)

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