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Eprex(Erythropoietin)8000 IU/0,8 ml (67,2 mcg) x 6(Cilag AG International)

Item 12684



Identifiers Symbols EPO; EP; MGC138142; MVCD2

External OMIM133170 MGI95407 HomoloGene624

IDs GeneCards: EPO Gene

 

Gene Ontology

Molecular function

erythropoietin receptor binding
hormone activity
protein binding
eukaryotic cell surface binding

Cellular component

extracellular region
extracellular space

Biological process

response to hypoxia
regulation of transcription from RNA polymerase II promoter
signal transduction
embryo implantation
aging
response to nutrient
blood circulation
positive regulation of cell proliferation
response to salt stress
negative regulation of sodium ion transport
erythrocyte differentiation
negative regulation of ion transmembrane transporter activity
response to lipopolysaccharide
response to vitamin A
response to testosterone stimulus
positive regulation of tyrosine phosphorylation of Stat5 protein
hemoglobin biosynthetic process
negative regulation of apoptosis
erythrocyte maturation
neuroprotection
response to estrogen stimulus
positive regulation of neuron differentiation
positive regulation of DNA replication
positive regulation of transcription, DNA-dependent
positive regulation of Ras protein signal transduction
response to axon injury
response to electrical stimulus
response to hyperoxia
response to interleukin-1
cellular hyperosmotic response

 


Erythropoietin, or its alternatives erythropoetin or erthropoyetin (play /ɨˌrɪθrɵˈpɔɪ.ɨtɨn/, /ɨˌrɪθrɵˈpɔɪtən/, or /ɨˌriːθrɵ-/) or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine for erythrocyte (red blood cell) precursors in the bone marrow.

Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and tubular epithelial cells. It is also produced in perisinusoidal Ito cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. Erythropoietin is the hormone that regulates red blood cell production. It also has other known biological functions. For example, erythropoietin plays an important role in the brain's response to neuronal injury.[1] EPO is also involved in the wound healing process.[2]

When exogenous EPO is used as a performance-enhancing drug, it is classified as an erythropoiesis-stimulating agent (ESA). Exogenous EPO can often be detected in blood, due to slight difference from the endogenous protein, for example in features of posttranslational modification.

History

In 1906, Paul Carnot, a professor of medicine in Paris,France, and his assistant DeFlandres proposed the idea that hormones regulate the production of red blood cells. After conducting experiments on rabbits subject to bloodletting, Carnot and DeFlandre attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto continued to study red cell production and later called the hemopoietic substance ‘erythropoietin’. Further studies investigating the existence of EPO by Reissman, and Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was finally purified and confirmed as erythropoietin, opening doors to therapeutic uses for EPO in diseases like anemia.[3][4]

Haematologist John Adamson and nephrologist Joseph W. Eschbach looked at various forms of renal failure and the role of the natural hormone EPO in the formation of red blood cells. Studying sheep and other animals in the 1970s, the two scientists helped establish that EPO stimulates the production of red cells in bone marrow and could lead to a treatment for anemia in humans. In 1968, Goldwasser and Kung began work to purify human EPO, and managed to purify milligram quantities of over 95% pure material by 1977.[5] Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.[6] Later an NIH-funded researcher at Columbia University discovered a way to synthesize EPO. Columbia University patented the technique, and licensed it to Amgen. Controversy has ensued over the fairness of the rewards that Amgen reaped from NIH-funded work, and Goldwasser was never financially rewarded for his work.[7]

In the 1980s, Adamson, Joseph W. Eschbach, Joan C. Egrie, Michael R. Downing and Jeffrey K. Browne conducted a clinical trial at the Northwest Kidney Centers for a synthetic form of the hormone, Epogen produced by Amgen. The trial was successful, and the results were published in the New England Journal of Medicine in January 1987.[8]

In 1985, Lin et al. isolated the human erythropoietin gene from a genomic phage library and were able to characterize it for research and production.[9] Their research demonstrated that the gene for erythropoietin encoded the production of EPO in mammalian cells that is biologically active in vitro and in vivo. The industrial production of recombinant human erythropoietin (RhEpo) for treating anemia patients would begin soon after.

In 1989, the U.S. Food and Drug Administration approved the hormone, called Epogen, which remains in use today.

Novel erythropoiesis stimulating protein

More recently, a novel erythropoiesis-stimulating protein (NESP) has been produced.[10] This glycoprotein demonstrates anti-anemic capabilities and has a longer terminal half-life than erythropoietin. NESP offers chronic renal failure patients a lower dose of hormones to maintain normal hemoglobin levels.

Regulation

EPO is produced mainly by peritubular capillary lining cells of the renal cortex; which are highly specialized epithelial-like cells. It is synthesized by renal peritubular cells in adults, with a small amount being produced in the liver.[11][12] Regulation is believed to rely on a feed-back mechanism measuring blood oxygenation. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors (HIFs), are hydroxylated and proteosomally digested in the presence of oxygen.[6] It binds to the erythropoietin receptor (EpoR) on the red cell surface and activates a JAK2 cascade. This receptor is also found in a large number of tissues such as bone marrow cells and peripheral/central nerve cells, many of which activate intracellular biological pathways upon binding with Epo.

Primary role in red cell blood line

Erythropoietin has its primary effect on red blood cells by promoting red blood cell survival through protecting these cells from apoptosis. It also cooperates with various growth factors involved in the development of precursor red cells. Specifically, the colony forming unit-erythroid (CFU-E) is completely dependent on erythropoietin. The burst forming unit-erythroid (BFU-E) is also responsive to erythropoietin.

Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E, pro-erythroblast and basophilic erythroblast subsets in the differentiation.

It has a range of actions including vasoconstriction-dependent hypertension, stimulating angiogenesis, and inducing proliferation of smooth muscle fibers. It has also been shown that erythropoietin can increase iron absorption by suppressing the hormone hepcidin.[13]

Uses

Erythropoietin is available as a therapeutic agent produced by recombinant DNA technology in mammalian cell culture. It is used in treating anemia resulting from chronic kidney disease and myelodysplasia, from the treatment of cancer (chemotherapy and radiation). Current research suggests that, aminoacid R103 to E mutation in Erythropoietin makes it Neuroprotective and non-erythropoietic.

Available forms as biomedicine

  • Erypro Safe, made by Biocon Ltd.
  • Repoitin, made by Serum Institute of India Limited
  • Eprex, made by Janssen-Cilag
  • NeoRecormon, made by Hoffmann–La Roche
  • Vintor, made by Emcure Pharmaceuticals
  • Epofit, made by Intas pharma
  • Erykine, made by Intas Biopharmaceutica
  • Wepox, made by Wockhardt Biotech
  • Epogen, made by Amgen
  • Espogen, made by LG life sciences.
  • ReliPoietin, made by Reliance Life Sciences
  • Shanpoietin, made by Shantha Biotechnics Ltd
  • Zyrop, made by Cadila Healthcare Ltd.
  • Epotrust, made by Panacea Biotec

Anemia due to chronic kidney disease

In patients who require dialysis (have stage 5 chronic kidney disease(CKD)), iron should be given with erythropoietin.[14] Dialysis patients in the US are most often given Epogen; outside of the US other brands of epoetin may be used.

Outside of people on dialysis, erythropoietin is used most commonly to treat anemia in people with chronic kidney disease who are not on dialysis (those in stage 3 or 4 CKD and those living with a kidney transplant). There are two types of erythropoietin for people with anemia due to chronic kidney disease (not on dialysis):

Brands in Epoetin Alpha are:

  • Epofit (Intas pharma)
  • Epoetin (Procrit (also known as Eprex),
  • Darbepoetin (Aranesp)

Brands in Epoetin Beta are:

  • NeoRecormon is Epoetin Beta
  • MIRCERA is Methoxy Polyethylene Glycol-Epoetin Beta

Anemia due to treatment for cancer

In March 2008, a panel of advisers for the U.S. Food and Drug Administration (FDA) supported keeping ESAs from Amgen and Johnson & Johnson on the market for use in cancer patients. The FDA has focused its concern on study results showing an increased risk of death and tumor growth in chemo patients taking the anti-anemia drugs. According to the FDA, evidence for increased rates of mortality exist in various cancers, including breast, lymphoid, cervical, head and neck, and non-small-cell lung cancer.[15]

Anemia in critically ill patients

There are two types of erythropoietin (and several brands) for people with anemia, due to critical illness. These are:

In a randomized controlled trial,[18] erythropoietin was shown to not change the number of blood transfusions required by critically ill patients. A surprising finding in this study was a small mortality reduction in patients receiving erythropoietin. This result was statistically significant after 29 days but not at 140 days. This mortality difference was most marked in patients admitted to the ICU for trauma. The authors speculate several hypotheses for potential etiologies of this reduced mortality, but, given the known increase in thrombosis and increased benefit in trauma patients as well as marginal nonsignificant benefit (adjusted hazard ratio of 0.9) in surgery patients, it could be speculated that some of the benefit might be secondary to the procoagulant effect of erythropoetin. Regardless, this study suggests further research may be necessary to see which critical care patients, if any, might benefit from administration of erythropoeitin. Any benefit of erythropoetin must be weighed against the 50% increase in thrombosis, which has been demonstrated in numerous trials[citation needed].

Blood doping

ESAs have a history of use as blood doping agents in endurance sports such as horseracing, boxing.[19] ,cycling, rowing, distance running, race walking, cross country skiing, biathlon, and triathlons.

Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly test for it, until in 2000, when a test developed by scientists at the French national anti-doping laboratory (LNDD) and endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by distinguishing it from the nearly identical natural hormone normally present in an athlete’s urine.

In 2002, at the Winter Olympic Games in Salt Lake City, Don Catlin, MD, the founder and then-director of the UCLA Olympic Analytical Lab, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first time in sports.[20]

In 2010, Floyd Landis admitted to using performance-enhancing drugs, including EPO, throughout the majority of his career as a professional cyclist.[21]

Since 2002, EPO tests performed by U.S. sports authorities have consisted of only a urine or “direct” test. From 2000–2006, EPO tests at the Olympics were conducted on both blood and urine.[22][23]

Neurological diseases

Erythropoietin has been shown to be beneficial in certain neurological diseases like schizophrenia.[24] Research has suggested that EPO improves the survival rate in children suffering from cerebral malaria, caused by the malaria parasite's blocking of blood vessels in the brain.[25][26][27]

Adverse effects

Erythropoietin is associated with an increased risk of adverse cardiovascular complications in patients with kidney disease if it is used to increase hemoglobin levels above 13.0 g/dl.[28]

Early treatment with erythropoietin correlated with an increase in the risk of Retinopathy of prematurity in premature infants who had anemia of prematurity, raising concern that the angiogenic actions of erythropoietin may exacerbate retinopathy.[29][30] However, since anemia itself increases the risk of retinopathy, the correlation with erythropoietin treatment may be incidental, and merely reflect that anemia induces retinopathy.

Safety advisories in anemic cancer patients

Amgen sent a "dear doctor" letter in January 2007 that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.

Amgen advised the U.S. Food and Drug Administration (FDA) regarding the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional cancer control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).

In response to these advisories, the FDA released a Public Health Advisory[31] on March 9, 2007, and a clinical alert[32] for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents (ESAs) such as epogen and darbepoetin. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

In addition, on March 9, 2007, drug manufacturers agreed to new black box warnings about the safety of these drugs.

On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.

Several publications and FDA communications have increased the level of concern related to adverse effects of ESA therapy in selected groups. In a revised Black Box Warning, the FDA notes significant risks associated with ESA use. ESAs should be used only in patients with cancer when treating anemia specifically caused by chemotherapy, and not for other causes of anemia. Further, it states that ESAs should be discontinued once the patient's chemotherapy course has been completed.[33][34][35][36]

Interactions

Erythropoietin has been shown to interact with the Erythropoietin receptor as its mechanism of action within the body.[37][38]

Drug interactions with Erythropoietin include: Major interaction:Lenalidomide--risk of thrombosis Moderate interaction:Cyclosporine--risk of high blood pressure may be greater in combination with EPO. EPO may lead to variability in blood levels of cyclosporine. Minor interactions: ACE inhibitors may interfere with hematopoiesis by decreasing the synthesis of endogenous erythropoietin or decreasing bone marrow production of red blood cells.[39]

See also

References

1.       ^ Siren AL et al. (2001). "Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress". Proc Natl Acad Sci USA 98 (7): 4044–4049. doi:10.1073/pnas.051606598. PMC 31176. PMID 11259643.

2.       ^ Haroon ZA, Amin K, Jiang X, Arcasoy MO (September 2003). "A novel role for erythropoietin during fibrin-induced wound-healing response". Am. J. Pathol. 163 (3): 993–1000. PMC 1868246. PMID 12937140.

3.       ^ Jelkmann W (March 2007). "Erythropoietin after a century of research: younger than ever". European journal of haematology 78 (3): 183–205. doi:10.1111/j.1600-0609.2007.00818.x. PMID 17253966.

4.       ^ Ahmet Höke (2005). Erythropoietin and the Nervous System. Berlin: Springer. ISBN 0-387-30010-4. OCLC 64571745.

5.       ^ Miyake T; Kung, CK; Goldwasser, E (Aug 1997). "Purification of human erythropoietin". J. Biol. Chem. 252 (15): 5558–5564. PMID 18467.

6.       ^ a b Jelkmann W (March 2007). "Erythropoietin after a century of research: younger than ever". Eur. J. Haematol. 78 (3): 183–205. doi:10.1111/j.1600-0609.2007.00818.x. PMID 17253966.

7.       ^ Angell, Marcia (2005). The Truth About the Drug Companies : How They Deceive Us and What to Do About It. New York: Random House Trade Paperbacks. p. 60. ISBN 0-375-76094-6.

8.       ^ Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial". N. Engl. J. Med. 316 (2): 73–8. doi:10.1056/NEJM198701083160203. PMID 3537801.

9.       ^ Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (November 1985). "Cloning and expression of the human erythropoietin gene". Proc. Natl. Acad. Sci. U.S.A. 82 (22): 7580–4. doi:10.1073/pnas.82.22.7580. PMC 391376. PMID 3865178.

10.   ^ Macdougall IC (July 2000). "Novel erythropoiesis stimulating protein". Semin. Nephrol. 20 (4): 375–81. PMID 10928340.

11.   ^ Jacobson LO, Goldwasser E, Fried W, Plzak L (March 1957). "Role of the kidney in erythropoiesis". Nature 179 (4560): 633–4. doi:10.1038/179633a0. PMID 13418752.

12.   ^ Fisher JW, Koury S, Ducey T, Mendel S (October 1996). "Erythropoietin production by interstitial cells of hypoxic monkey kidneys". British journal of haematology 95 (1): 27–32. doi:10.1046/j.1365-2141.1996.d01-1864.x. PMID 8857934.

13.   ^ Ashby DR, Gale DP, Busbridge M, et al. (March 2010). "Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin". Haematologica 95 (3): 505–8. doi:10.3324/haematol.2009.013136. PMC 2833083. PMID 19833632.

14.   ^ Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE (1996). "A randomized controlled study of iron supplementation in patients treated with erythropoietin". Kidney Int. 50 (5): 1694–9. doi:10.1038/ki.1996.487. PMID 8914038.

15.   ^ Smith A (2008-03-13). "FDA panel gives surprise OK to Amgen and J&J: FDA panelists support keeping Amgen, J&J drugs on market - Mar. 13, 2008". CNNMoney.com. Retrieved 2009-03-31.

16.   ^ "Procrit (Epoetin alfa)". Ortho Biotech Products. Retrieved 2009-04-29.[dead link]

17.   ^ "Aranesp(darbepoetin alfa)". Amgen.com. Retrieved 2009-04-29.

18.   ^ Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ (September 2007). "Efficacy and safety of epoetin alfa in critically ill patients". The New England Journal of Medicine 357 (10): 965–76. doi:10.1056/NEJMoa071533. PMID 17804841.

19.   ^ "Boxing Scandals". Bleacher Report. 2011-12. Retrieved 2011-12-22.

20.   ^ Steeg JL (2007-02-28). "Catlin has made a career out of busting juicers - USATODAY.com". USA TODAY. Retrieved 2009-03-31.

21.   ^ "Landis admits to illegal drug use". BBC News. 2010-05-20.

22.   ^ Lasne F, Martin L, Crepin N, de Ceaurriz J (December 2002). "Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones". Anal. Biochem. 311 (2): 119–26. doi:10.1016/S0003-2697(02)00407-4. PMID 12470670.

23.   ^ Kohler M, Ayotte C, Desharnais P, Flenker U, Lüdke S, Thevis M, Völker-Schänzer E, Schänzer W (January 2008). "Discrimination of recombinant and endogenous urinary erythropoietin by calculating relative mobility values from SDS gels". Int J Sports Med 29 (1): 1–6. doi:10.1055/s-2007-989369. PMID 18050057.

24.   ^ Ehrenreich H, Degner D, Meller J, et al. (January 2004). "Erythropoietin: a candidate compound for neuroprotection in schizophrenia" (PDF). Molecular psychiatry 9 (1): 42–54. doi:10.1038/sj.mp.4001442. PMID 14581931.

25.   ^ Casals-Pascual C, Idro R, Picot S, Roberts DJ, Newton CR (2009). "Can erythropoietin be used to prevent brain damage in cerebral malaria?". Trends Parasitol 25 (1): 30–6. doi:10.1016/j.pt.2008.10.002. PMID 19008152.

26.   ^ Core A, Hempel C, Kurtzhals JA, Penkowa M (2011). "Plasmodium berghei ANKA: erythropoietin activates neural stem cells in an experimental cerebral malaria model.". Exp Parasitol 127 (2): 500–5. doi:10.1016/j.exppara.2010.09.010. PMID 21044627.

27.   ^ "Kidney drug could save children from malaria brain damage". The Guardian.

28.   ^ Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A (2006). "Normalization of hemoglobin level in patients with chronic kidney disease and anemia". N. Engl. J. Med. 355 (20): 2071–84. doi:10.1056/NEJMoa062276. PMID 17108342.

29.   ^ Ohlsson A, Aher SM (2006). "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants". Cochrane Database Syst Rev 3: CD004863. doi:10.1002/14651858.CD004863.pub2. PMID 16856062.

30.   ^ Aher SM, Ohlsson A (2006). "Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants". Cochrane Database Syst Rev 3: CD004865. doi:10.1002/14651858.CD004865.pub2. PMID 16856063.

31.   ^ "FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)". Archived from the original on 2007-05-28. Retrieved 2007-06-05.

32.   ^ "Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA)". Archived from the original on 2007-05-15. Retrieved 2007-06-05.

33.   ^ "Erythropoiesis Stimulating Agents: Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa)". MedWatch - 2007 Safety Information Alerts. U.S. Food and Drug Administration. 2008-01-03. Retrieved 2009-04-09.

34.   ^ "Procrit (Epoetin alfa) for injection". U.S. Food and Drug Administration. 2007-08-11. Retrieved 2009-04-09.[dead link]

35.   ^ "Aranesp (darbepoetin alfa) for Injection". U.S. Food and Drug Administration. 2007-11-08. Retrieved 2009-04-09.[dead link]

36.   ^ "Information on Erythropoiesis Stimulating Agents (ESA) (marketed as Procrit, Epogen, and Aranesp)". U.S. Food and Drug Administration. 2009-01-26. Retrieved 2009-04-09.

37.   ^ Middleton, S A; Barbone F P, Johnson D L, Thurmond R L, You Y, McMahon F J, Jin R, Livnah O, Tullai J, Farrell F X, Goldsmith M A, Wilson I A, Jolliffe L K (May. 1999). "Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide". J. Biol. Chem. (UNITED STATES) 274 (20): 14163–9. doi:10.1074/jbc.274.20.14163. ISSN 0021-9258. PMID 10318834.

38.   ^ Livnah, O; Johnson D L, Stura E A, Farrell F X, Barbone F P, You Y, Liu K D, Goldsmith M A, He W, Krause C D, Pestka S, Jolliffe L K, Wilson I A (Nov. 1998). "An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation". Nat. Struct. Biol. (UNITED STATES) 5 (11): 993–1004. doi:10.1038/2965. ISSN 1072-8368. PMID 9808045.

39.   ^ Drug Interactions of Erythropoietin Alfa at Drugs.com

Further reading

  • Takeuchi M, Kobata A (1992). "Structures and functional roles of the sugar chains of human erythropoietins.". Glycobiology 1 (4): 337–46. doi:10.1093/glycob/1.4.337. PMID 1820196.
  • Semba RD, Juul SE (2002). "Erythropoietin in human milk: physiology and role in infant health.". Journal of human lactation : official journal of International Lactation Consultant Association 18 (3): 252–61. PMID 12192960.
  • Ratcliffe PJ (2003). "From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway.". Blood Purif. 20 (5): 445–50. doi:10.1159/000065201. PMID 12207089.
  • Westenfelder C (2003). "Unexpected renal actions of erythropoietin.". Exp. Nephrol. 10 (5-6): 294–8. doi:10.1159/000065304. PMID 12381912.
  • Becerra SP, Amaral J (2002). "Erythropoietin--an endogenous retinal survival factor.". N. Engl. J. Med. 347 (24): 1968–70. doi:10.1056/NEJMcibr022629. PMID 12477950.
  • Genc S, Koroglu TF, Genc K (2004). "Erythropoietin and the nervous system.". Brain Res. 1000 (1-2): 19–31. doi:10.1016/j.brainres.2003.12.037. PMID 15053948.
  • Fandrey J (2004). "Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression.". Am. J. Physiol. Regul. Integr. Comp. Physiol. 286 (6): R977–88. doi:10.1152/ajpregu.00577.2003. PMID 15142852.
  • Juul S (2004). "Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models.". Clinics in perinatology 31 (1): 129–42. doi:10.1016/j.clp.2004.03.004. PMID 15183662.
  • Buemi M, Caccamo C, Nostro L, et al. (2005). "Brain and cancer: the protective role of erythropoietin.". Med Res Rev 25 (2): 245–59. doi:10.1002/med.20012. PMID 15389732.
  • Sytkowski AJ (2007). "Does erythropoietin have a dark side? Epo signaling and cancer cells.". Sci. STKE 2007 (395): e38. doi:10.1126/stke.3952007pe38. PMID 17636183.

 

Erythropoietin (EPO) and EPO Test

 

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Definition of Erythropoietin

 

Erythropoietin (EPO) is a hormone produced by the kidney that promotes the formation of red blood cells by bone marrow (bone marrow).

 

Kidney cells that make erythropoietin is specialized so that they are sensitive to oxygen levels are low in the blood that flows through the kidneys. These cells make and release erythropoietin when oxygen levels are too low. Low oxygen levels may indicate anemia, a number of red blood cells are reduced, or molecules of hemoglobin that carries oxygen throughout the body.

 

Erythropoietin (EPO) in Chemistry

 

Erythropoietin is a protein with an attached sugar (a glycoprotein). He is one of a number of similar glycoproteins that serve as a stimulus-stimulus (stimulus) for the growth of specific types of blood cells in the bone marrow.

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Task Erythropoietin (EPO)

 

Erythropoietin stimulating (stimulating) bone marrow (bone marrow) to produce more red blood cells. An increase that results from it in the red cells increases the capacity of the blood to carry oxygen.

 

As the primary regulator of red cell production, erythropoietin main functions are to:

 

1. Advance the development of red blood cells.

2. Starting the synthesis of hemoglobin, the molecule in red blood cells that transports oxygen.

 

The only source of kidneys of erythropoietin?

 

No. Erythropoietin is produced at a lesser extent by the liver. Only about 10% of erythropoietin is produced in the liver. Erythropoietin gene has been found on human chromosome 7 (in band 7q21). A series of different DNA flanking the erythropoietin gene acts to control the production of erythropoietin from the liver opponent of the kidney.

 

Why Erythropoietin test done?

 

The hormone erythropoietin can be detected and measured in the blood. Levels of erythropoietin in the blood can indicate bone marrow disorders (such as polycythemia, or red blood cell production increases), kidney disease, or misuse of erythropoietin. Testing blood levels of erythropoietin so is worth it if:

 

* Too little erythropoietin may be responsible for too few red blood cells (as in evaluating anemia, especially anemia associated with kidney disease).

* Too much of erythropoietin may cause too many red blood cells (polycythemia).

* Too much of erythropoietin may be evidence for a kidney tumor.

* Too much of erythropoietin in an athlete (athlete) may suggest misuse of erythropoietin.

 

How Erythropoietin test done?

 

Usually Patients were asked to fast 8-10 hours (overnight) and sometimes lie down quietly and relax for 20 or 30 minutes before tests. The test requires a routine blood sample, which is sent to a lab for analysis.

Normal erythropoietin levels?

 

Normal levels of erythropoietin ranged from 4 to 24 mU / ml (milliunits per milliliter).

Abnormal erythropoietin levels? Indicates What?

 

Lower than normal values ​​erythropoietin seen, for example, in anemia caused by chronic renal failure (prolonged).

 

Erythropoietin levels that rise can be seen, for example, in polycythemia rubra vera, a disorder characterized by an excess of red blood cells.

 

The correct interpretation of an abnormal erythropoietin levels depending on the specific clinical situation.

Can Someone Without A Disease or Medical Condition Which Erythropoietin Have A Higher Rate?

 

Yes. For example, erythropoietin has been misused as a drug that enhances performance on the sports teams such as bicycle racers (on Tour), long-distance runners, jogger, skater, and players Nordic skiing (cross-country). If misused in these types of situations, especially the danger of erythropoietin is thought (probably because of dehydration caused by heavy exercise can further increase the thickness (viscosity) of blood, raising the risk for heart attack and seranga-strokes). Erythropoietin has been banned by organizations Tour, Olympics, and other sports.

 

Erythropoietin Is Available For A Prescribed Drugs?

 

Yes. Using recombinant DNA technology, erythropoietin has been produced synthetically for use as a treatment for people with certain types of anemia. Erythropoietin can be used to correct the anemia by stimulating red blood cell production in bone marrow in these conditions. The medicine is known as epoetin alfa (Epogen, Procrit). He can be given as an injection intravenously or subcutaneously (under the skin).

 

The use of Erythropoietin-Clinical Use

 

Erythropoietin [epoetin alfa (Epogen, Procrit)] is used in many installation-fitting clinic. The most common use is in people with anemia associated with abnormal function (dysfunction) kidney. When the kidneys are not functioning properly, they produce less than normal amounts of erythropoietin, which can lead to the production of red blood cells are low, or anemia. Therefore, by replacing erythropoietin with an injection of synthetic erythropoietin, anemia associated with kidney disease may be treated. Today, Epogen or Procrit is a standard part of therapy in patients with kidney disease who require dialysis to both treat and prevent anemia.

 

Other uses of erythropoietin may include treatment of anemia associated with AZT treatment (used to treat AIDS) and cancer-related anemia.


EPO Blood Building - The New Rage In Bodybuilding And Sports Supplements!


One of the hottest topics capturing the attention of athletes, coaches and trainers centers on using the drug rhEPO. Discover how blood building is becoming a hot topic for debate as athletes continue looking for the edge. Find out more.

By: Daniel Gastelu Feb 04, 2009

Authors Note: One of the fastest growing sports supplement product categories consists of "vasoactive" products, such as Nitric Oxide (NO) boosters, which are involved in improving blood flow, increasing the "Muscle Pump" and have other physiological functions.

Another new innovation in sports nutrition supplementation gaining popularity is aimed at increasing "Blood Building" via simulation of the body's red blood cell building hormone - Erythropoietin.

This article focuses on this newest trend of blood building sports supplements and related synergistic NO boosting benefits - Dual Action EPO and Nitric Oxide Stimulation.


EPO Blood Building
The New Rage In Bodybuilding And Sports Supplements!

One of the hottest topics capturing the attention of athletes, coaches and trainers centers on using the drug rhEPO (recombinant erythropoietin). EPO (erythropoietin) is a hormone that is naturally produced in the body and primarily functions to stimulate the production of new red blood cells.

Increasing the amount of red blood cells increases the oxygen carrying capacity of the blood to deliver more oxygen to exercising muscles. The extra oxygen significantly increases the muscles' energy production and can therefore help to improve athletic performance output ability; higher intensity and longer duration. These benefits have led to the widespread use of synthetic rhEPO drug doping.

Due to the increase in oxygen carrying capacity and other vasoactive effects of interest, EPO has also gained interest among athletes outside of the endurance crowd; strength athletes, including bodybuilders, who are looking to increase exercise intensity, training session volume and quality of their workouts and those who are equally interested in achieving the "perpetual pump".

But there are even more interesting aspects to the EPO blood boosting story, including combating the fatigue causing drop in pH levels, a synergistic Nitric Oxide connection and enhanced nutrient delivery to stimulate muscle growth.


EPO-Red Blood Cells-Oxygen

From a straightforward athletic performance bio-energetic perspective, oxygen is required for the body to make energy (aerobically) to produce muscle contractions, in addition to anaerobic produced energy.

Within muscle cells, there are energy producing structures called mitochondria. Oxygen is used inside the mitochondria to drive the biochemical reactions that breakdown carbohydrates, fats and certain amino acids to produce energy in the form of ATP (adenosine tri-phosphate). This enables the body to convert the energy stored in foods to a form it can use in the body in the form of ATP.

These high energy ATP molecules are then used by the muscles as an energy source to power muscle contractions. So, more oxygen in the body/muscles yields more ATP generation, increasing muscle contractions, which results in improving athletic performance. This benefit of increasing oxygen in the body has lead to the reported use or suspected use of rhEPO by top endurance athletes.

Now, with the sports authorities cracking down on illegal rhEPO used in sports and the additional risk of potential harmful side effects of using rhEPO unsupervised, athletes are seeking alternative ways for boosting their own EPO and red blood cells, in addition to boosting their nitric oxide (NO) levels.


Natural EPO/Red Blood Cell Boosting

Athletes are now turning to natural EPO/red blood cell boosting performance enhancing products as alternatives to using the drug form, rhEPO. Sports science researchers have discovered that certain natural substances and nutrients can increase EPO levels, red blood cell production, plus additional related benefits for maximum endurance output, including increased blood flow.

Sports Performance Benefits of EPO

Medically, rhEPO is used to increase red blood cell count. Logically, since EPO accelerates red blood cell production, it also increases the oxygen carrying capacity of the blood and more oxygen to muscles and other tissues of the body. This primary benefit of rhEPO attracted the attention of the athletic community and led to the use (or alleged) of rhEPO by elite athletes.

Endurance Athletes and rhEPO

The use of rhEPO is reported by the athletic community to help increase oxygen carrying capacity of the blood, by building more red blood cells thereby improving athletic performance and reducing exercise fatigue.

This enables performance improvements in endurance type and other sports because of the extra oxygen carrying capacity. It is also believed that rhEPO and naturally produced EPO increases the metabolism and the healing process of muscles because the extra red cells carry more oxygen and nutrients, improving recovery ability.

Hardcore Bodybuilders Underground Use of EPO Boosting

Bodybuilders and other strength athletes using testosterone replacement drugs have long known the benefits of boosting EPO and red blood cells, as this is a secondary effect of this category of drugs.

Prior to the development of rhEPO, the popular anabolic steroid Anadrol was used to increase red blood cells. Anadrol has a reputation in bodybuilding for producing the best pumps and extreme vascularity. In addition to increasing muscle size and strength, noticeable improvements in workout endurance are reported to occur. To maximize these steroid induced EPO benefits, actual rhEPO use is suspected to be on the rise among bodybuilders and strength athletes.

Natural EPO Boosting Is The New Way To Go

The newest trend among rhEPO using athletes is to use legal specialized sports nutrition supplements designed to naturally boost their production of EPO. In taking the sports supplement route to boost their body's ability to maximize EPO, red cell building and oxygen uptake, this avoids taking illegal performance enhancing drug products.


Red Blood Cell (Erythrocytes) Building

Red blood cells, also known as erythrocytes or red corpuscles, primarily function in the transport of oxygen and carbon dioxide in the body. The red blood cells are specialized types of cells that are loaded with a substance called hemoglobin. Naturally produced EPO in the body stimulates the production of red blood cells from stem cells that originate in bone marrow.

OXYGEN TRANSPORTATION ARTICLE

Because blood cells have a short life in the bloodstream (only a few to several weeks) it is important to optimize this blood building process to maintain an optimum level of red blood cells. This is of particular importance to people who are more physically active, such as athletes, because intensive exercise will increase the breakdown of red blood cells.

Furthermore, it is additionally beneficial to maintain optimum levels of nutrients and substances that increase the red blood cell building stem cell populations, as well as to protect red blood cells once they are produced and delivered into the bloodstream.

Major Function of Hemoglobin

The major function of the hemoglobin molecules found densely packed in red blood cells is the transport of oxygen from the lungs through the bloodstream to the tissues and trillions of cells in the body.

During hemoglobin's functioning in the body, it will alternate between two physiological states based on if it is carrying oxygen molecules or not; oxyhemoglobin and deoxyhemaglobin. In the oxyhemoglobin state, hemoglobin is loaded up with oxygen. In the deoxyhemoglobin state, hemoglobin is devoid of oxygen, which is also known as empty hemoglobin.

Biochemically, hemoglobin is a specialized protein molecule, a conjugated globular protein, which consists of heme groups containing iron.

The iron components of hemoglobin function to "lock-on" to oxygen and also on to carbon dioxide molecules. Therefore, adequate dietary/supplement intake of iron is vital for the development and functioning of red blood cells. Forms such as ferrous fumarate are used in supplements as an "organic" alternative to iron oxide and other inorganic forms.

Carbon Dioxide Transport and Hemoglobin

In addition to carrying molecules of oxygen, hemoglobin also transports the metabolic waste product carbon dioxide from cells through the bloodstream and to the lungs where it is exhaled into the atmosphere. (Yes, humans are a source of CO2, refer to my related podcast about this).

As CO2 tissue levels build up during exercise, this contributes to the onset of fatigue, reducing the ability to maintain high-normal levels of exercise/athletic performance. It is therefore of paramount importance to have high levels of red blood cells, plus good blood circulation, to create the conditions in the bloodstream that will rapidly clear away CO2 from exercising muscles and eliminate it from the body.


Natural EPO and Red Blood Boosters

In a quest to find natural alternatives to rhEPO, that is, substances to naturally enhance EPO levels and boost red blood cell production, there is a growing list of research backed ingredients. Here are some nutrients/ingredients found in sports supplements that are reported to boost EPO and red blood cell production, function and duration, as well as produce other benefits of interest to athletes.

Arachidonic Acid:

The EPO production stimulating effects of Arachidonic Acid are attributed to its involvement in the biochemical process leading to the actual production of EPO in the body and phospholipase activation in erythroid progenitor cell proliferation. Arachidonic Acid is abundant in the body and involved in many structural and biochemical functions.

Regarding EPO production, Arachidonic Acid is the precursor molecule in the production of eicosanoids, which are substances in the body found to be involved in stimulating the production of EPO. Additionally, recent research has reported anabolic muscle-building effects of Arachidonic Acid.

Cobalt:

Cobalt is another key research based EPO/red blood cell production stimulator, which is needed by humans in small amounts. It is also a necessary component of vitamin B12. In the research report titled "Blood Doping by Cobalt", researchers reported that cobalt is a naturally occurring element that enhances erythropoiesis and angiogenesis (growth of new blood vessels), resulting in increasing red blood cell concentration and circulation. The proposed mechanisms of action include more efficient transcription of the erythropoietin gene.

Echinacea:

More recent research has demonstrated that Echinacea stimulates production of erythroid (red blood cell) growth factors, induces erythropoiesis and increases the oxygen-transport capacity of the blood, in addition to its well-known role for beneficially stimulating the immune system.

The blood building and improved oxygen carrying capacity effects of taking standardized Echinacea supplements was reported in a recent study using male subjects. This research, along with other research studies, has found that the use of Echinacea containing supplements increased EPO levels, interleukin-3 (IL-3) levels, increased red blood cell count, increased the number and size of red blood cells, and increased maximal oxygen consumption VO2 max.

Niacin:

This essential vital vitamin that is required by the body for the formation of coenzymes NAD and NADP. Niacin also has vasodilation properties, especially for dilating the micro-circulatory system that is responsible for the delivery of oxygen, nutrients, and hormones to the muscle cells and clearance of metabolic waste products.

Portulaca Oleracea:

This botanical contains high concentration flavones that scientific research reports may improve the expression level of EPO and accelerate the generation of erythrocytes and hemoglobin.

Vitamin B-6 (As Pyridoxine HCl And Pyridoxine 5-Phosphate):

An essential vitamin needed for red blood cell production. Vitamin B-6 also helps increase the amount of oxygen carried by hemoglobin (the iron containing oxygen transport metallo-protein in red blood cells). Note that a vitamin B-6 deficiency can result in some health problems.

Vitamin B-12 (Methylcobalamin, Cyanocobalamin, Dibencozide):

This essential vitamin is vital for red blood cell production. Deficiency in Vitamin B-12 is responsible for a reduction in red blood cells and can lead to muscle fatigue and weakness.


EPO Blood Building and the Synergistic Effects of Nitric Oxide

While EPO and NO boosting have well-known distinct benefits, the question arises if boosting both EPO and NO will produce synergistic effects? The answer is unequivocally yes!

Let's examine how these two performance agents work in tandem to give athletes a new competitive edge. Here's a short recap of the science of NO. Major attention was first directed to NO when the Nobel Prize in Physiology or Medicine in 1998 was awarded to Robert F. Furchgott, Louis J. Ignarro and Ferid Murad for their discoveries concerning "the nitric oxide as a signaling molecule in the cardiovascular system".

One of the main functions performed by NO in the cardiovascular system is dilating blood vessels. This function helps to increase blood flow to muscle and other tissues in the body.

As more research has been focused on NO, more functions have been identified, such as NO's role as an important signaling molecule outside the cardiovascular system; signaling between nerve cells in the brain, enhancing the olfactory sense and immune system functioning.

Chief among NO's many functions in the sports nutrition product industry is its role in vasodilation - leading to achieving the resistance exercise induced PUMP. Vasodilating during exercise is vital to accommodate increasing blood volume and enhance blood flow rate for maximum delivery of oxygen, nutrients and anabolic hormones to muscle tissue, as well as improve metabolic waste clearance, such as fatigue causing carbon dioxide.

So, while EPO boosting provides a means to stimulate more red blood cells and higher nutrient and oxygen carrying capacity, NO provides the means to widen the blood vessels to promote greater blood flow. In this way, EPO and NO working together are the vasoactive cart and horse of maximizing performance enhancing enriched blood and blood vessel super-pumps.

Nitric oxide stimulates the blood vessel dilating effects, to create a wider circulatory system conduit for the EPO stimulated red blood cell enriched volumized bloodstream to deliver more oxygen and nutrients to the muscles and other tissues, with a new level of performance expected from these synergistic effects.

There are now hundreds of products featuring ingredients for promoting NO mediated vasodilation, primarily by two modes of action; precursors that are involved in NO production, and stimulators that are involved in stimulating the production of NO. Here are some of effective ingredients found being used in NO stimulating products, and are also contained in the newest class of dual action EPO - NO stimulating products.


NO Boosting Ingredients

Arginine:

Arginine is the key amino acid that is used to make nitric oxide in your body. NO products found on the shelves usually contain Arginine as a single ingredient or in other forms, for example, Arginine Alpha Keto Glutarate and Arginine Ethyl Ester.

Some products contain a multi-source Arginine blend claiming to ensure fast, complete and sustained absorption of the arginine molecule provided in free form and special organic complexes, such as with Alpha Keto Glutarate and Ethyl Ester for dynamic physiological action.

Citrulline:

Citrulline is another amino acid found in NO stimulating supplements, primarily for its purported function of boosting the body's arginine levels and thereby supporting the NO production pathway.

Citrulline can be used on its own as a supplement, but it is typically included along with Arginine and other NO stimulating ingredients as a way of saturating the nitric oxide production pathways to ensure that peak nitric oxide production is achieved, as arginine has a variety of other functions in the body, in addition to NO production.

Citrulline also has other roles in the body that can benefit athletic performance, such as anti-fatigue properties in detoxification of ammonia amon.

Cnidium Monnier:

This botanical ingredient is reported to be traditionally used to support already normal male sexual performance. However, modern research determined that a primary physiological function of this botanical is to increase the release of Nitric Oxide by cells lining the circulatory system, thereby promoting vasodilation.

This NO boosting effect reveals a viable reason for its traditional use for promoting normal male sexual function, as well as an ingredient used in NO boosting sports nutrition products.

Folate:

This essential vitamin is involved in the hematopoietic system and is required for red blood cell production. Folate also has beneficial effects on endothelial function, as measured with the use of flow-mediated dilatation (FMD).

A recent study reported that folic acid improved endothelial function and increased flow-mediated dilation. Folate also lowers homocysteine levels, which is beneficial because a high level of homocysteine impairs cardiovascular function and blood flow. Furthermore, research revealed that folic acid is involved in the regeneration of tetrahydrobiopterin, which enhances nitric oxide synthase function and maximizes nitric oxide production.

Gynostemma Pentaphyllum:

Gypenosides extracted from Gynostemma pentaphyllum have been shown to elicit vasorelaxation and vasodilation through the direct release of endothelium-derived nitric oxide. In this way Gynostemma serves to directly stimulate NO levels in the cardiovascular system and plays a synergistic role with NO precursor substances, like arginine.

NorValine:

Norvaline is related to the branched chain amino acid Valine. Norvaline functions to inhibit the arginase enzyme, thus increasing arginine levels available for NO production. Norvaline can in this way optimize the NO boosting effects of a multi-ingredient NO boosting formula, in particular in formulas containing arginine and or citrulline, by optimizing the NO synthesizing biochemical pathway.

Methyltetrahydrofolate:

Methyltetrahydrofolate is reported to be a specialized bioactive compound found in specialized products that claims to have the unique ability to maximize the conversion of arginine to NO by augmenting all of the co-factors involved in arginine's conversion to Nitric Oxide within the series of biochemical pathways.

While arginine is the primary precursor used by the body to produce Nitric Oxide, there are other interactions along the Nitric Oxide synthesis pathway which influences Nitric Oxide production; both positive (NOS-Nitric Oxide Synthase) and negative or inhibitory factors (ADMA-asymmetric dimethylarginine and SOA-super oxide anion).

Vasofolate functions to increase the amount of arginine that converts into NO by combating negative factors, such as ADMA and SOA, which optimizes nitric oxide production biochemical pathways. Vasofolate is also reported to increase NOS-Nitric Oxide Synthase activity, which can further increase the production of NO.


Effects of Nitric Oxide Stimulation On Blood Vessels Compared to EPO + NO Stimulation.

Nitric Oxide Stimulation

A blood vessel will be vasodilated from boosting Nitric Oxide levels. Without EPO stimulated blood building, there is a potential dilution effect of red blood cells and other substances in the bloodstream.

Dual Action EPO and Nitric Oxide Stimulation

A blood vessel will be in a "super-vasodilated" state from the synergistic effects of boosting Nitric Oxide levels, plus EPO stimulated blood building bloodstream contents. EPO stimulated red blood cells and other substances that may increase from the blood building effect may further enhance blood vessel dilation.

Dual Action EPO and Nitric Oxide Stimulation

Comparison Of Nitric Oxide Stimulation VS
Dual Action EPO and Nitric Oxide Stimulation.


Exercise / Athletic Performance Significance

While NO boosting has well-established benefits in promoting vasodilation, there are additional important synergistic benefits for boosting EPO, red blood cell building, and red blood cell life span in the bloodstream.

NO mediated vasodilation alone will only provide minimal bloodstream related beneficial effects, unless red blood cell building and blood volume is also increased via EPO mediated and related physiological stimuli. For the advanced athlete, the overall benefits of maximizing EPO, red blood cell content, blood volume, NO, vasodilating, anabolic hormone levels, nutrients, and metabolic waste clearance can include:

    • Increase oxygen carrying capacity for improved muscle endurance and work load.
    • Increase removal of metabolic waste to prevent muscle fatigue and allow for greater workout capacity and muscle growth stimulation.
    • Greater energy production to exercise harder more intensely.
    • Enhancement of both the anaerobic and aerobic biogenic exercise capacity of muscle for maximum force production, lifting heaver workloads, and performing more reps and sets.
    • Improved recovery between sets and workouts.
    • Increase VO2max.
    • Increase muscle building potential.
    • Reducing training-induced red blood cell breakdown.
    • Promotion of Angiogenesis (new blood vessel formation).
    • Improved athletic performance.

Therefore, by ensuring that EPO mediated "blood building" is maximized, this can in turn optimize the vasodilation effects of NO to achieve a new level of exercise and athletic performance.

References

  1. Beckman, B. and Nystuen L. Comparative effects of inhibitors of arachidonic acid metabolism on erythropoiesis. Prostaglandins Leukot Essent Fatty Acids. 1988 Jan;31(1):23-26.
  2. Beckman, BS, and Seferynska, I. Possible involvement of phospholipase activation in erythroid progenitor cell proliferation. Exp. Hmeatol. 1989 Mar;17(3):309-312.
  3. Beleslin-Cokic, BB., et al. Erythropoietin and hypoxia stimulate erythropoietin, receptor and nitric oxide production by endothelial cells. Blood 2004 Oct 1;104(7):2073-80.
  4. Bucher, M., et al. Cobalt but not hypoxia stimulates PDGF gene expression in rats. Am J Physiol. 1996 Sep;271:E451-7.
  5. Chung, Y., et al. Control of respiration and bioenergetics during muscle contraction. Am J Physiol Cell Physiol. 2005 Mar 288:C730-C738.
  6. Connes, P., et al. Faster oxygen uptake kinetics at the onset of submaximial cycling exercise following 4 weeks recombinant human erythropoietin treatment. Pflugers Arch. 2003 Nov;447(2)231-8.
  7. Desplat, V., et al. Effects of lipoxygenase metabolites of arachidonic acid on the growth of human blood CD34 progenitors. Blood Cells, Molecules, and Diseases. 2000;Oct 26(5):427-436.
  8. Dong, LW., et al. Effects of flavones extracted from Portulaca oleracea on ability of hypoxia tolerance in mice and its mechanisms. Zhong Xi Yi Jie He Xue Bao. 2005; 3(6):450-4.
  9. Fisher, JW. Erythropoietin: Physiology and Pharmacology Update. Exp Biol Med. 2003 228:1-14.
  10. Fisher, JW., et al. A concept for the control of kidney production of erythropoietin involving prostagladins and cyclic nucleotides. Contrib Nephrol. 1978;13:37-59.
  11. Foley, JE., The effects of arachidonic acid on erythropoietin production in exhypoxic polycythemic mice and the isolated perfused canine kidney. J Pharmacol Exp Ther. 1978 Nov;207(2):402-9.
  12. Goldwasser, E., et al. Studies on erythropoiesis V. The effect of cobalt on the production of erythropoietin. Blood 1958; 13:55-60.
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  14. Jelkmann, W. Molecular biology of erythropoietin. Internal Medicine 2004 Aug 43(8):649-659.
  15. Kao, R., et al. Erythropoietin improves skeletal muscle microcirculation and tissue bioenergetics in a mouse sepsis model. Crit Care. 2007;11(3):R58.
  16. Kim, SW., et al. Direct and indirect effects of androgens on survival of hematopoietic progenitor cells in vitro. J Korean Med Sci. 2005 Jun;20(3):409-16.
  17. Lappin, TR., et al. EPO's alter ego: erythropoietin has multiple actions. Stem Cells 2002;20:485-492.
  18. Lippi, G., et al. Blood doping by cobalt. Should we measure cobalt in athletes? Journal of Occupational Medicine and Tox. 2006;1:18.
  19. Lippi, G. and Cuidi, CG. Gene manipulation and improvement of athletic performances: new strategies in blood doping. Br J Sports Med 2004: 38:641.
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  21. Miller, ME., et al. Mechanism of erythropoietin production by cobalt. Blood. 1974 Sept 44(3):339-346.
  22. Navarro, JF., et al. Randomized prospective comparison between erythropoietin and androgens in CAPD patients. Kidney Int. 2002 Apr;61(4):1537-44.
  23. Pringle, JS., et al. Oxygen uptake kinetics during moderate, heavy and severe "submaximal" exercise humans: the influence of muscle fiber type and capillarisation. Eur J Appl Physiol. 2003 May;89(3-4):289-300.
  24. Roberts, MD., et al. Effects of arachidonic acid supplementation on training adaptations in resistance-trained males. Journal of the International Society of Sports Nutrition 2007, 4:21.
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  26. Snyder, DS and Desforges JF. Lipoxygenase metabolites of arachidonic acid modulate hematopoiesis. Blood. 1986 Jun;67(6):1675-1679.
  27. Teruel, JL., et al. Androgen therapy for anaemia of chronic renal failure. Indications in the erythropoietin era. Scan J Urol Nephrol. 1996 Oct;30(5):403-8.
  28. Whitehead MT., et al. The effect of 4 wk of oral Echinacea supplementation on serum erythropoietin and indices of erythropoietic status. Int J Sport Nutr Exerc Metab. 2007 Aug;17(4):378-90.
  29. Wojchowski, DM and He, TC., Signal transduction in the erythropoietin receptor system. Stem Cells. 1993 Vol 11, 381-392.

 

"Genetic Doping" with erythropoietin cDNA in primate muscle is detectable

Françoise Lasne1, Laurent Martin1, Jacques de Ceaurriz1, Thibaut Larcher2, Philippe Moullier2,3 and Pierre Chenuaud2

  1. 1National Anti-Doping Laboratory, 92290 Chatenay-Malabry, France
  2. 2INSERM U 649, CHU Hotel-Dieu, 44035 Nantes, France
  3. 3EFS Pays de Loire, 44035 Nantes, France

Correspondence: Françoise Lasne/Philippe Moullier, Laboratoire de Therapie Genique, Inserm U649, CHU Hotel-Dieu, Bat. J. Monnet, 30 boulevard Jean Monnet, 44035 Nantes, Cedex 01, France

Received 23 June 2004; Accepted 20 July 2004.

Forthcoming "genetic doping" is predicted to be undetectable. In the case of recombinant human erythropoietin (rhEPO), a hormone used in endurance sports, it is being predicted that exogenous drug injections will be replaced by the transfer of the corresponding gene into some of the athlete's own cells. The hormone thus produced inside the organism is assumed to be completely identical to the physiological one. Our results show that this is not the case and open up optimistic prospects for antidoping control involving gene transfer.

Doping in sport, with very few exceptions, arises from misused medical treatments. This is the case for rhEPO, a hormone that stimulates red blood cell production and that has become a key element of doping in endurance sports. Treatment with rhEPO currently requires repeated injections of recombinant hormones obtained from nonhuman cells, i.e., Chinese hamster ovary (CHO) and baby hamster kidney (BHK) cells, into which the human gene of the hormone has been inserted. Natural endogenous and rhEPO were shown to present different isoelectric profiles, probably the result of altered posttranslational modifications that are species- and tissue type-dependent. This difference has allowed for the development of a test to detect the presence of rhEPO in urine, a test that is currently used in antidoping controls1.

Genetic technologies are expected to change the very nature of medical treatments. For instance, it is now conceivable that administration of an exogenous therapeutic protein will be replaced by introducing the corresponding gene into some of the patient's own cells. It is almost inevitable that athletes will exploit such medical progress in an effort to elude detection by sport authorities charged with curbing doping practices. Doping practices, in addition to being the focus of regulatory issues, may also severally and adversely affect the health of athletes that engage in such practices. Doping by gene transfer may compound these adverse side effects because of direct toxic effects, persistent gene expression, or potential insertional mutagenesis2,3. Furthermore, the assumption that these new methods of doping will yield proteins that are identical to the endogenous gene product, thus making detection impossible, may not be the case.

To compare the isoelectric profiles of physiological EPO and hormone resulting from in vivo gene transfer, we have adapted for serum analysis a method previously developed for urine4. Using this method, samples from cynomolgus macaques were analyzed for the serum recombinant EPO profile before and after transfer of the homologous cDNA into skeletal muscle by injection of recombinant adeno-associated virus5. Transgene expression was controlled by a doxycycline-regulatable system6.

The physiological isoforms of the simian hormone were very similar to those of human urine EPO (Fig. 1b). Induction of transgene expression in these macaques resulted in overexpression of a hormone presenting a pattern strikingly different from that of the endogenous isoforms (Fig. 1c). The transgene-derived isoforms resolved with isoelectric focusing at higher pH, a finding more characteristic of recombinant EPO than endogenous EPO (Fig. 1a). In primates, EPO is primarily synthesized by renal peritubular fibroblasts7. The distinctive isoelectric pattern of recombinant EPO produced by skeletal muscle emphasizes the importance of cell type on the characteristics of recombinant EPO.

Figure 1.

Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Isoelectric patterns of erythropoietin. (a) rhEPO from CHO cells (lane 1) and BHK cells (lane 2). (b) Physiological EPO from human urine (lane 3) and macaque serum (lanes 4 and 5). (c) EPO from macaque serum after gene transfer in skeletal muscle (lanes 6 and 7). Serum samples (5) and (6) are from the same animal before and after gene transfer, respectively. Specific detection of EPO was obtained by double-blotting following isoelectric focusing. Cathode is at the top.

It is noteworthy that the structural features responsible for the described differences between the isoelectric patterns of physiological human urinary EPO and those of recombinant hormone are not yet clarified4. The newly observed differences in the macaque serum between the pattern of physiological EPO and that from transduced muscle are every bit as striking and require further study. Because a previous report8 indicated that EPO extracted from serum was not as different in isoform distribution from recombinant EPO as was urinary EPO, the difference that we report here between the endogenous and the transgene-derived product from the serum samples is even more relevant. However, because the current test for rhEPO in sport uses urine, our study will have to be extended to this biological fluid.

The biological effects of recombinant EPO from genetically engineered muscle have been demonstrated in animal models9,10. However, our observations indicate that this recombinant EPO, like the other sources of rhEPO, is not identical to the physiological hormone. Skeletal muscle, since it is an easily accessible and efficiently transduced tissue, is likely to be the target tissue of choice for genetic doping. Although other methods of gene transfer exist and may be exploited for gene doping, and such methods are yet to be investigated, our results provide encouraging evidence that doping by gene transfer will likely not go undetected at least when skeletal muscle is the target.

References

  1. Lasne, F. and de Ceaurriz, J. (2000). Recombinant erythropoietin in urine. Nature. 405: 635. | Article | PubMed | ISI | ChemPort |
  2. Lippi, G. and Guidi, G. (2003). New scenarios in antidoping research. Clin. Chem. 49: 2106–2107. | Article | PubMed | ChemPort |
  3. McCrory, P. (2003). Super athletes or gene cheats? Br. J. Sports Med. 37: 192–193. | Article | PubMed | ChemPort |
  4. Lasne, F., Martin, L., Crepin, N. and de Ceaurriz, J. (2002). Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones. Anal. Biochem. 311: 119–126. | Article | PubMed | ChemPort |
  5. Chenuaud, P., et al. (2004). Autoimmune anemia in macaques following erythropoietin gene therapy. Blood. 103: 3303–3304. [Published online January 22, 2004].  | Article | PubMed | ISI | ChemPort |
  6. Chenuaud, P., et al. (2004). Optimal design of a single recombinant adeno-associated virus derived from serotypes 1 and 2 to achieve more tightly regulated transgene expression from nonhuman primate muscle. Mol. Ther. 9: 410–418. | Article | PubMed | ISI | ChemPort |
  7. Fisher, J. (2003). Erythropoietin: physiology and pharmacology update. Exp. Biol. Med. 288: 1–14.
  8. Skibeli, V., Nissen-Lie, G. and Torjesen, P. (2001). Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin. Blood. 98: 3626–3634. | Article | PubMed | ChemPort |
  9. Samakoglu, S., Bohl, D. and Heard, J. M. (2002). Mechanisms leading to sustained reversion of beta-thalassemia in mice by doxycycline-controlled Epo delivery from muscles. Mol. Ther. 6: 793–803. | Article | PubMed | ChemPort |
  10. Johnston, J., Tazelaar, J., Rivera, V., Clackson, T., Gao, G. and Wilson, J. (2003). Regulated expression of erythropoietin from an AAV vector safely improves the anemia of beta-thalassemia in a mouse model. Mol. Ther. 7: 493–497. | Article | PubMed | ChemPort |


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