Physiology Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

News Physiol Sci 18: 201-204, 2003; doi:10.1152/nips.01448.2003
1548-9213/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (34)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aw, T. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aw, T. Y.
News in Physiological Sciences, Vol. 18, No. 5, 201-204, October 2003
© 2003 Int. Union Physiol. Sci./Am. Physiol. Soc.

Cellular Redox: A Modulator of Intestinal Epithelial Cell Proliferation

Tak Yee Aw

Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130

   Abstract
 
Mucosal proliferation, together with differentiation and apoptosis, are a continuous homeostatic process in the intestinal epithelium. The glutathione/glutathione disulfide redox status plays a key role in intestinal growth control wherein a reduced redox potential maintains a proliferative state. An oxidative shift in this potential elicits growth arrest and cell transition to a differentiated or apoptotic phenotype.


   Introduction
Top
 Introduction
Control of cellular redox...
 Cell responses to redox...
 Summary and perspectives
 References
 
Tissue oxidative stress, which results from a disturbance in the cellular prooxidant-antioxidant balance in favor of prooxidants, is an important contributor to the genesis of gut pathologies such as inflammation and cancer (1). That hydroperoxy and hydroxy fatty acids can provoke colonic DNA synthesis and induction of ornithine decarboxylase (3) is consistent with stimulation of proliferative responses associated with oxidant challenge and underscores the tumorigenic potential of these reactive species. This consideration is pertinent to the intestine, whose epithelium often encounters oxidants like lipid peroxides of dietary or endogenous origin. Because oxidative stress induces changes in cellular oxidation-reduction (redox) events, these findings highlight a role for redox in the control of intestinal epithelial proliferative activity. The current review will focus on the concepts salient to understanding control of cellular redox homeostasis, the relationship between cellular redox and cell proliferation, and how a loss of this redox balance alters intestinal cell proliferative responses. This knowledge underpins the centrality of cellular redox in governing cell growth.


   Control of cellular redox homeostasis
Top
 Introduction
 Control of cellular redox...
Cell responses to redox...
 Summary and perspectives
 References
 
Glutathione and thiol redox balance.
The tripeptide glutathione (known as {gamma}-glutamylcysteinylglycine or GSH) is the major low-molecular-weight thiol in cells that controls cellular thiol-disulfide redox state, which is essential for normal redox signaling (9). The dynamics of cellular redox balance are achieved by maintenance of the thiol-to-disulfide status of reduced GSH and its oxidized form, GSSG. Oxidation-reduction and thiol-disulfide exchange reactions during oxidative perturbations will cause a redistribution of GSH and GSSG; the resultant quantitative shift in the ratio of GSH to GSSG in favor of GSSG directly reflects an oxidized redox status and is a convenient expression of oxidative stress within a cell. The redox potential (Eh), which takes into consideration the stoichiometry of two GSH oxidized per GSSG formed, is another useful quantitative expression for the redox state of the GSH/GSSG pool. Eh is calculated by the Nernst equation: Eh = Eo + (RT/nF)ln([GSSG]/[GSH]2) (9) (where Eo is the standard potential for the redox couple at defined pH, R is the gas constant, T is the absolute temperature, F is Faraday’s constant, and n is the number of electrons transferred), and cellular estimates of Eh for the GSH/GSSG redox couple are in the range of -260 to -200 mV. During oxidative stress, intracellular GSSG accumulates (Fig. 1Go), and the loss of thiol redox balance will elicit deleterious consequences for metabolic regulation, cellular integrity, and organ homeostasis. The regulation of intestinal thiol redox balance is a complex process, and apart from the GSH/GSSG couple, the cysteine/cysteine redox redox pair is also an important contributor to control of intestinal thiol/disulfide balance.



View larger version (21K):
[in this window]
[in a new window]
  		FIGURE 1. Maintenance of cellular reduced GSH status during oxidative challenge. Coupling of GSH redox cycle to NADPH supply is shown. During peroxide elimination, the regeneration of GSH from GSSG is maintained by the GSH peroxidase and GSSG reductase system, the GSH redox cycle. The continued function of the redox cycle activity is dependent on the availability of NADPH, of which the pentose phosphate pathway is a major source. The cellular rate of NADPH supply is regulated by glucose flux in the pathway and the activity of glucose-6-phosphate dehydrogenase.

 
NADPH maintains cellular GSH/GSSG redox.
Tissue GSH status is maintained in the reduced state by the GSH peroxidase and GSSG reductase system, commonly known as the GSH redox cycle, which is coupled to the oxidized and reduced nicotinamide dinucleotide phosphate (NADP+/ NADPH) redox pair (Fig. 1Go). The GSH redox cycle is the major mechanism for maintenance of cellular GSH homeostasis during oxidant challenge such as occurs with peroxide exposure. The availability of GSH to support redox cycle activity depends on the supply of NADPH (Fig. 1Go), and an increased cellular GSSG resulting from enhanced peroxide stress will activate pentose phosphate shunt activity. Increases in NADPH production rates are dependent on glucose availability and the function of the redox-sensitive glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pathway. Consequently, the metabolic fate of intestinal cells (proliferation or apoptosis) induced by a disrupted GSH-to-GSSG balance may be highly sensitive to the cellular rate of NADPH supply and the threshold at which the supply of both glucose and NADPH (and thus GSH) are superseded by demand.


   Cell responses to redox imbalance
Top
 Introduction
 Control of cellular redox...
 Cell responses to redox...
Summary and perspectives
 References
 
Redox status governs differential cell transition to proliferative or apoptotic states.
The fate of cells in multicellular organisms is decided by survival or promoting signals. Whereas survival signals mediate cell maintenance through influencing metabolic events, promoting signals direct targeted cells toward proliferation, differentiation, transformation, or death by apoptosis. Fully differentiated tissues like the liver, kidney, brain, and intestine are characterized by cells arrested in the quiescent state, and imposition of severe oxidative stress often results in a cytotoxic biological endpoint. However, necrotic death is not necessarily an obligatory endpoint of all oxidative stress. Indeed, subtoxic oxidative stress and mild redox shifts can induce transition of a cell from a quiescent state to that of a proliferative or apoptotic state. Prevailing evidence shows that shifting control checkpoints in the direction of reduction or oxidation (i.e., to a relatively more negative or positive Eh, respectively) results in a cell that favors quiescence, proliferation, growth arrest, differentiation, or apoptosis (Ref. 2; Fig. 2Go). Terminally quiescent cells like hepatocytes exhibit a biological constraint to proliferate due to a mitotic block (Fig. 2Go, curve I). An elevation in oxidation toward a more positive Eh induces cell progression to growth arrest, differentiation, or death by apoptosis. A genetic program in mitotically competent cells signals cell proliferation in response to an antigenic, mitogenic, or redox stimulus (Fig. 2Go, curve II). These initial stimuli may provide the "priming" event that lowers the barrier of cell cycle regulatory checkpoints (e.g., G0/G1 transition) that subsequently drive the cell to proliferate. Intestinal cells, because of their high turnover rate, represent such a cell type wherein subtoxic oxidant challenge causes a sufficient oxidative shift in the cellular redox that allows for enhanced mitogenic response. Whereas transformed or tumor cells normally exhibit few barriers to proliferation, a subtoxic oxidant dose with the associated mild redox shift could provide a stimulus for further growth potential or push the cell beyond the maximal point of damage that initiates the apoptotic phase (Fig. 2Go, curve III). Anticancer drugs are known principally to operate by "forcing" actively proliferating tumor cells into apoptosis (10); whether cellular redox mediates this cell transition is unclear. Collectively, these examples illustrate the fundamental concept that cellular responses to oxidative stress and redox imbalance are not linear but are bell-shaped, and, depending on the severity of redox shift, proliferation, differentiation, or apoptosis may predominate.



View larger version (21K):
[in this window]
[in a new window]
  		FIGURE 2. Cellular responses to GSH/GSSG redox status and steady-state redox potential (Eh) for the cellular GSH/GSSG pool at different cell stages. A: fully differentiated cells are typically arrested in the quiescent state. Changes in the cellular GSH/GSSG redox state can initiate cell proliferation, growth arrest/differentiation, or apoptosis, depending on the cell type and the magnitude of the redox imbalance. Curves I, II, and III, respectively, represent terminally differentiated, mitotically competent, and transformed cell types. Adapted from Ref. 2. B: cells undergo a progression from a reduced to an oxidized state (i.e., from a more negative to a more positive Eh) as they transition from proliferation to growth arrest/differentiation to apoptosis. Proliferating cells exhibit ~50 mV more reduced potential than differentiated and growth-arrested cells, and the Eh in apoptotic cells is further oxidized by ~50 mV relative to growth-arrested cells. Redrawn from Ref. 9.

 
Cellular redox in modulation of intestinal proliferation.
An interesting aspect of cellular redox is that Eh varies with cell growth status. For instance, cells that are rapidly proliferating exhibit an ~50 mV more reduced potential than differentiated and growth-arrested cells, and the Eh in apoptotic cells is further oxidized by ~50 mV relative to growth-arrested cells (Refs. 9 and 13; Fig. 2BGo). Thus the cellular redox status would provide a physiological context for cell regulation that optimizes the thiol-disulfide control of metabolic and signaling pathways, transcription factor activation, and cell growth. Considerable literature evidence supports redox signaling mechanisms in cell growth control. That GSH precursors or increasing cellular GSH can enhance cell proliferation is consistent with a relationship between cellular GSH concentration and proliferation (8). Actively proliferating fibroblast cells exhibit high intracellular GSH levels that decrease as cells become quiescent during serum starvation (17). The requirement for growth factor stimulation is associated with elevated cellular GSH that is correlated with enhanced DNA synthesis and cell entry into the S phase (17). Depletion of GSH inhibits cell growth; this antiproliferative effect is reversed by supplemental GSH or GSH precursors in conjunction with normalization of cellular GSH (17). GSH effects in cell proliferation have been associated with autophosphorylation of growth factor receptor and stimulation of protein kinase C activity (7). Apart from cellular GSH, changes in the GSH/GSSG redox state have been implicated in cell cycle responses that include proliferation, differentiation, and apoptosis in that a progression from a more reducing to a more oxidizing GSH/GSSG redox state occurs as cells transition from proliferation through contact inhibition, differentiation, and apoptosis. Curiously, replicative senescence, which is associated with a slowing of cell division, population doubling, and growth, elicits an increase rather than a decrease in cellular GSH-to-GSSG status (4).

Intestinal epithelial proliferation, differentiation, and apoptosis are a continuous homeostatic process, and a role for the cellular GSH/GSSG redox status has been implicated in these cell stages. The fundamental concept that changes in GSH/GSSG modulate intestinal cell growth and arrest comes from studies with cultured intestinal cells. Treatment of Caco-2 cells with low lipid peroxide levels (1–5 µM) promote proliferative activity that tracks directly with the induction of cellular GSH/GSSG imbalance (6). As the peroxide induces a progressive oxidized shift in the GSH/GSSG redox state, cells progress from proliferation to growth arrest (6). Importantly, the redox (or Eh) threshold governing the transition point between cell proliferation and growth arrest is considerably lowered in cells when their intracellular GSH concentrations are compromised (14); consequently, populations of proliferating cells that possess low baseline cellular GSH are selectively vulnerable to oxidizing events that readily elicit cell cycle arrest and induce cell transition to a differentiated or apoptotic phenotype. Studies in animal models similarly support a paradigm of redox modulation of intestinal proliferative function in vivo. Rats placed chronically on a lipid peroxide diet exhibited marked suppression of intestinal mucosal ornithine decarboxylase activity (an enzyme marker of intestinal proliferation) in accordance with an oxidized tissue GSH/GSSG redox state (18). This oxidant-induced epithelial growth arrest was ameliorated on restoration of tissue GSH/GSSG redox balance by supplemental GSH (18), consistent with a close association between intestinal proliferative activity and the mucosal redox state.

Apart from redox control mediated by intracellular GSH/GSSG status, two other important aspects of redox regulation in cell proliferation are worthy of mention. The first is the redox modulation of extracellular signals such as receptor activation and function. Growth factor-induced intestinal proliferation has been shown to involve changes in extracellular Eh that are distinct from the intracellular redox status (12, 13). Moreover, changes in the extracellular cysteine-to-cystine redox status per se have been shown to mediate proliferative signaling that is independent of the intracellular GSH/GSSG status (15). Second, much attention has been focused on the thioredoxin (Trx)/Trx reductase redox system in the control of cell proliferation, particularly in cancer cells wherein Trx expression is high (16). Trx is a tightly conserved low-molecular-weight protein that possesses a redox active dithiol/disulfide site; in normal cells, Trx is ideally suited for influencing the redox state of catalytic or structural thiol moieties of proteins. The Trx/Trx reductase system complements the GSH/GSSG system, and among its many cellular roles this redox protein functions to maintain redox-sensitive transcription factors in their reduced, active forms. Interestingly, whereas Trx has a pivotal function in cellular thiol-disulfide regulation, recent evidence shows that the Trx redox status is minimally affected as intestinal cells progress from proliferation to differentiation despite significant oxidation of the GSH/GSSG redox state (13). The results suggest that the dynamics of intestinal cell growth control by the cellular Trx redox regulating system may be functionally dissociated from that of the GSH/GSSG system.

Redox signaling.
The elucidation of redox signaling mechanisms in cell proliferation is a major challenge for cell biologists and cell physiologists. The mammalian response to stress is complex and often involves multiple signaling pathways that act in concert to determine cell fate. Oxidants can trigger phosphorylation cascades that lead to activation of mitogen-activated protein kinases (MAPKs) and the nuclear factor {kappa}B (NF-{kappa}B), implying their involvement in redox signaling. A direct role for redox activation of MAPK signaling pathways remains unresolved despite their sensitivity to oxidants and the finding that MAPKs can be activated following GSH oxidation. Of the different MAPKs, the extracellular signal-regulated protein kinase that is often associated with survival and growth signaling shows greater activation in response to mitogenic stimulation; whether this proliferative response involves redox participation is unclear. The redox-sensitive NF-{kappa}B is among the potential MAPK-regulated transcription factors known to be activated in response to oxidative stress, suggesting that it plays a role in determining cell fate during oxidative or redox stress. Although it is well appreciated that NF-{kappa}B is activated by oxidants, a direct response of the transcription factor to cellular redox changes is less well studied. Existing evidence in the literature suggests a possible link between cellular thiol redox status and NF-{kappa}B-mediated gene expression in that altered GSH-to-GSSG ratio has been shown to activate NF-{kappa}B (11). Akt is a well-studied serine/threonine protein kinase protooncogene whose function has been implicated in cellular survival (5). To date, little is known of Akt function to coordinate redox signaling with intestinal cell survival or changes in cell cycle or ploidy.


   Summary and perspectives
Top
 Introduction
 Control of cellular redox...
 Cell responses to redox...
 Summary and perspectives
References
 
Early data from animal studies clearly underscore the tumorigenic potential of dietary oxidants in the development of gut pathology, but the molecular mechanism for oxidant-induced increase in mucosal proliferative potential is unresolved. Recent advances in free radical biology research have implicated a redox mechanism in the loss of homeostatic control of intestinal epithelial cell proliferation. Evidence to date support a major role for cellular GSH/GSSG redox status in the control of intestinal growth and cellular transition to growth-arrested and apoptotic phenotypes. The current paradigm is consistent with maintenance of a highly reduced Eh (~260 mV) in actively proliferating cells. An oxidative shift in Eh, such as occurs during oxidant challenge, induces cell progression through to the growth arrest, differentiation, or apoptosis stages in accordance with the magnitude of this redox shift. The notion that cellular GSH/GSSG imbalance can be normalized by supplemental GSH suggests a potential for GSH therapy in the maintenance of tissue redox integrity and homeostasis of epithelial proliferation in the intestinal epithelium.


   Acknowledgments
 
Research in my laboratory was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-44510 and DK-43785).


   References
Top
 Introduction
 Control of cellular redox...
 Cell responses to redox...
 Summary and perspectives
 References
 

  1. Ames B. Dietary carcinogens and anticarcinogens. Science221: 11256–11263, 1983.
  2. Aw TY. Molecular and cellular responses to oxidative stress and changes in oxidation-reduction imbalance in the intestine. Am J Nutr70: 551–565, 1999.
  3. Bull AW, Nigro ND, Golembieski WA, Crissman JD, and Marnett LJ. In vivo stimulation of DNA synthesis and induction of ornithine decarboxylase in rat colon by fatty acid hydro-peroxides autooxidation products of unsaturated fatty acids. Cancer Res44: 4924–4928, 1984.[Abstract/Free Full Text]
  4. Carlisle R, Rhoads CA, Aw TY, and Harrison L. Endothelial cells maintain a reduced redox environment even as mitochondrial function declines. Am J Physiol Cell Physiol283: C1675–C1686, 2002.[Abstract/Free Full Text]
  5. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, and Greenberg ME. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science275: 661–665, 1997.[Abstract/Free Full Text]
  6. Gotoh Y, Noda T, Iwakiri R, Fujimoto K, Rhoads CA, and Aw TY. Lipid peroxide-induced redox imbalance differentially mediates CaCo-2 cell proliferation and growth arrest. Cell Prolif35: 221–235, 2002.[Web of Science][Medline]
  7. Iantomasi T, Favilli F, Degl’Innocenti D, and Vincenvini MT. Increased glutathione synthesis associated with platelet-derived growth factor stimulation of NIH3T3 fibroblasts. Biochim Biophys Acta1452: 303–312, 1999.[Medline]
  8. Iwata S, Hori T, Sata N, Ueda-Taniguchi Y, Yamabe T, Nakamura H, Masutani H, and Yodoi J. Thiol-mediated redox regulation of lymphocyte proliferation: possible involvement of adult T-cell leukemia factor and GSH in transferrin receptor expression. J Immunol152: 5633–5642, 1994.[Abstract]
  9. Jones DP. Redox potential of GSH/GSSG couple: assay and biological significance. Methods Enzymol348: 93–112, 2002.[Web of Science][Medline]
  10. Kaufmann SH. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res49: 5870–5878, 1989.[Abstract/Free Full Text]
  11. Kokura S, Wolf RE, Yoshikawa T, Granger DN, and Aw TY. Molecular mechanisms of neutrophil-endothelial cell adhesion induced by redox imbalance. Circ Res84: 516–524, 1999.[Abstract/Free Full Text]
  12. Miller LT, Watson WH, Kirlin WG, Ziegler TR, and Jones DP. Oxidation of glutathione/glutathione disulfide redox state induced by cysteine deficiency in human colon carcinoma HT29 cells. J Nutr132: 2303–2306, 2002.[Abstract/Free Full Text]
  13. Nkabyo YS, Siegler TR, Li H, Watson WH, and Jones DP. Glutathione and thioredoxin redox during differentiation in a human colon carcinoma (CaCo-2) cell line. Am J Physiol Gastrointest Liver283: G1352–G1359, 2002.[Abstract/Free Full Text]
  14. Noda T, Iwakiri R, Fujimoto K, and Aw TY. Induction of mild intracellular redox imbalance inhibits proliferation of CaCo-2 cells. FASEB J15: 2131–2139, 2001.[Abstract/Free Full Text]
  15. Noda T, Iwakiri R, Fujimoto K, Rhoads CA, and Aw TY. Exogenous cysteine and cystine promote cell proliferation in CaCo-2 cells. Cell Prolif35: 117–129, 2002.[Web of Science][Medline]
  16. Powis G, Mustacich D, and Coon A. The role of the redox protein thioredoxin in cell growth and cancer. Free Rad Biol Med29: 312–322, 2000.[Web of Science][Medline]
  17. Shaw JP and Chou IN. Elevation of extracellular glutathione content associated with mitogenic stimulation of quiescent fibroblast. J Cell Physiol129: 193–198, 1986.[Web of Science][Medline]
  18. Tsunada S, Iwakiri R, Noda T, Fujimoto K, Fuseler J, Rhoads CA, and Aw TY. Chronic exposure to subtoxic levels of peroxidized lipids suppresses mucosal cell turnover in rat small intestine and reversal by glutathione. Dig Dis Sci48: 210–222, 2003.[Medline]



This article has been cited by other articles:


Home page
 FASEB J.Home page
S. J. James, S. Rose, S. Melnyk, S. Jernigan, S. Blossom, O. Pavliv, and D. W. Gaylor
Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism
FASEB J, August 1, 2009; 23(8): 2374 - 2383.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
C. Bauchart-Thevret, B. Stoll, S. Chacko, and D. G. Burrin
Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs
Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1239 - E1250.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
T. Kakimoto, T. Fujise, R. Shiraishi, T. Kuroki, J. M. Park, A. Ootani, Y. Sakata, S. Tsunada, R. Iwakiri, and K. Fujimoto
Indigestible Material Attenuated Changes in Apoptosis in the Fasted Rat Jejunal Mucosa
Experimental Biology and Medicine, March 1, 2008; 233(3): 310 - 316.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
L. Wang, Y. Tang, D. C. Rubin, and M. S. Levin
Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome
Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1559 - G1569.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. Tian, N. Washizawa, L. H. Gu, M. S. Levin, L. Wang, D. C. Rubin, S. Mwangi, S. Srinivasan, Y. Gao, D. P. Jones, et al.
Stimulation of colonic mucosal growth associated with oxidized redox status in rats
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1081 - R1091.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
J. Tian, N. Washizawa, L. H. Gu, M. S. Levin, L. Wang, D. C. Rubin, S. Mwangi, S. Srinivasan, D. P. Jones, and T. R. Ziegler
Local Glutathione Redox Status Does Not Regulate Ileal Mucosal Growth after Massive Small Bowel Resection in Rats
J. Nutr., February 1, 2007; 137(2): 320 - 325.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
M. S. Attene-Ramos, K. Kitiphongspattana, K. Ishii-Schrade, and H. R. Gaskins
Temporal changes of multiple redox couples from proliferation to growth arrest in IEC-6 intestinal epithelial cells
Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1220 - C1228.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
G. Wu, Y.-Z. Fang, S. Yang, J. R. Lupton, and N. D. Turner
Glutathione Metabolism and Its Implications for Health
J. Nutr., March 1, 2004; 134(3): 489 - 492.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (34)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aw, T. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aw, T. Y.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the Int. Union Physiol. Sci./Am. Physiol. Soc.