Abstract
Previous studies in healthy subjects have shown an increase in erythropoietin (EPO) production after administration of N-acetyl-cysteine (NAC). These authors hypothesized that NAC increases intracellular reduced glutathione, decreasing reactive oxygen species and enabling EPO production. We investigated if EPO production could be stimulated with a single dose of NAC, after 90 min of pure oxygen breathing. Thirty-eight healthy volunteers were randomized into either the control (C) group or the NAC group, which received 600 mg NAC PO dissolved in a glass of orange juice, 60 min before breathing 15 L/min of 100% normobaric oxygen. Orange juice was administered to both groups. Blood samples for EPO measurement were taken at T0, before the orange juice administration, and T1, T2, T3 and T4, respectively, 8, 24, 32 and 48 h after the orange juice. The EPO concentrations of the NAC group decreased significantly at T1, followed by a significant increase compared to baseline, which was obvious until T4. The EPO concentrations of the C group did not show any significant variations. In this study, a significant increase of EPO production was observed after a short-term hyperoxic stimulus only when preceded with the administration of a single dose of NAC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ando D, Yamakita M, Yamagata Z, Koyama K (2009) Effects of glutathione depletion on hypoxia-induced erythropoietin production in rats. J Physiol Anthropol 28:211–215
Balestra C, Germonpré P, Poortmans JR, Marroni A (2006) Serum erythropoietin levels in healthy humans after a short period of normobaric and hyperbaric oxygen breathing: the “normobaric oxygen paradox”. J Appl Physiol 100:512–518
Burk R (2007) Oxygen breathing may be a cheaper and safer alternative to exogenous erythropoietin (EPO). Med Hypotheses 69:1200–1204
Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH (2000) Hypoxia Inducible Factor-α Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor Protein. J Biol Chem 275:25733–25741
Ebert BL, Bunn HF (1999) Regulation of the erythropoietin gene. Blood 94:1864–1877
Embury SH, Garcia JF, Mohandas N, Pennathur-Das R, Clark M (1984) Effects of oxygen inhalation on endogenous erythropoietin kinetics, erythropoiesis, and properties of blood cells in sickle-cell anemia. N Engl J Med 311:291–295
Freudenthaler SM, Schreeb KH, Wiese A, Pilz J, Gleiter CH (2002) Influence of controlled hypoxia and radical scavenging agents on erythropoietin and malondialdehyde concentrations in humans. Acta Physiol Scand 174:231–235
Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC (2007) Acute postnatal ablation of Hif-2α results in anemia. Proc Natl Acad Sci USA 104:2301–2306
Haddad JJ (2002) Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology. Respir Res 3:26
Haddad JJ, Land SC (2000) O2-evoked regulation of HIF-1α and NF-κB in perinatal lung epithelium requires glutathione biosynthesis. Am J Physiol Lung Cell Mol Physiol 278:492–503
Haddad JJ, Olver RE, Land SC (2000) Antioxidant/pro-oxidant equilibrium regulates HIF-1α and NF-κB redox sensitivity: evidence for inhibition by glutathione oxidation in alveolar epithelial cells. J Biol Chem 275:21130–21139
Hildebrandt W, Alexander S, Bärtsch P, Dröge W (2002) Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O2 chemosensitivity. Blood 99:1552–1555
Huang LE, Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin–proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992
Kallio PJ, Wilson WJ, O’Brien S, Makino Y, Poellinger L (1999) Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin–proteasome pathway. J Biol Chem 274:6519–6525
Keramidas ME, Kounalakis SN, Debevec T, Norman B, Gustafsson T, Eiken O, Mekjavic IB (2011) Acute normobaric hyperoxia transiently attenuates plasma EPO concentration in healthy males: evidence against the “Normobaric Oxygen Paradox” theory. Acta Physiol. doi:10.1111/j.1748-1716.2011.02262.x
Niess AM, Fehrenbach E, Lorenz I, Müller A, Northoff H, Dickhuth HH, Schneider EM (2004) Antioxidant intervention does not affect the response of plasma erythropoietin to short-term normobaric hypoxia in humans. J Appl Physiol 96:1231–1235
Paliege A, Rosenberger C, Bondke A, Sciesielski L, Shina A, Heyman SN, Flippin LA, Arend M, Klaus SJ, Bachman S (2010) Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization. Kidney Int 77:312–318
Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH (2007) Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 117:1068–1077
Salceda S, Caro J (1997) Hypoxia-inducible factor-1α (HIF1-α) protein is rapidly degraded by the ubiquitin–proteasome system under normoxic conditions: its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272:22642–22647
Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, Shelton JM, Richardson JA, Moe O, Garcia JA (2005) HiF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood 105:3133–3140
Semenza GL (2009) Regulation of oxygen homeostasis by hypoxia-inducible factor-1. Physiology 24:97–106
Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454
Smith AH, Kark JD, Cassel JC, Spears GFS (1977) Analysis of prospective epidemiologic studies by minimum distance case–control matching. Am J Epidemiol 105:567–574
Tanimoto K, Makino Y, Pereira T, Poellinger L (2000) Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor protein. EMBO J 16:4298–4309
Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90:4304–4308
Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270:1230–1237
Wang GL, Jiang BH, Rue Ea, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514
Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, Eckardt KU (2004) Differentiating the functional role of hypoxia-inducible factor (HIF)-1α and HIF-2α (Epas-1) by the use of RNA interference: erythropoietin is a HIF-2α target gene in Hep 3B and Kelly Cells. FASEB J 18:1462–1464
Zembron-Lacny A, Slowinska-Lisowska M, Szygula Z, Witkowski K, Szyszka K (2009) The comparison of antioxidant and haematological properties of N-acetylcysteine and α-lipoic in physically active males. Physiol Res 58:855–861
Acknowledgments
Support was provided only from the departments of pneumology and anesthesiology.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Momeni, M., De Kock, M., Devuyst, O. et al. Effect of N-acetyl-cysteine and hyperoxia on erythropoietin production. Eur J Appl Physiol 111, 2681–2686 (2011). https://doi.org/10.1007/s00421-011-1893-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00421-011-1893-4