Identifiers Symbols EPO; EP;
MGC138142; MVCD2
External OMIM: 133170 MGI: 95407
HomoloGene: 624
IDs GeneCards: EPO
Gene
Erythropoietin, or its alternatives erythropoetin or erthropoyetin
(
/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
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Siren AL et al. (2001). "Erythropoietin
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PMID 11259643.
2. ^
Haroon ZA, Amin K, Jiang X, Arcasoy MO (September 2003). "A novel
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Am. J. Pathol. 163 (3): 993–1000. PMC 1868246.
PMID 12937140.
3. ^ Jelkmann W (March 2007). "Erythropoietin after a century of
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4. ^ Ahmet Höke (2005). Erythropoietin and the
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PMID 8857934.
13. ^
Ashby DR, Gale DP, Busbridge M, et al. (March
2010). "Erythropoietin
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14. ^
Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR,
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15. ^
Smith A (2008-03-13). "FDA
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Amgen, J&J drugs on market - Mar. 13, 2008". CNNMoney.com. Retrieved 2009-03-31.
16. ^
"Procrit
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17. ^
"Aranesp(darbepoetin
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18. ^
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"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
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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
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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.
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Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall
IC, Tsakiris D, Burger HU, Scherhag A (2006). "Normalization of hemoglobin
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Med. 355 (20): 2071–84. doi:10.1056/NEJMoa062276. PMID 17108342.
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Ohlsson A, Aher SM (2006). "Early erythropoietin for
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PMID 16856062.
30. ^
Aher SM, Ohlsson A (2006). "Early versus late
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31. ^ "FDA
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(marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)".
Archived from the
original on 2007-05-28. Retrieved
2007-06-05.
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Archived from the original
on 2007-05-15. Retrieved 2007-06-05.
33. ^
"Erythropoiesis
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Procrit (epoetin alfa)". MedWatch - 2007 Safety Information Alerts.
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"Procrit
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"Aranesp
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2007-11-08. Retrieved 2009-04-09.[dead link]
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"Information
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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.
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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.
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.
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.
|
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.
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.
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Randomized prospective comparison between erythropoietin and androgens
in CAPD patients. Kidney Int. 2002 Apr;61(4):1537-44.
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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
- 1National Anti-Doping Laboratory, 92290
Chatenay-Malabry, France
- 2INSERM U 649, CHU Hotel-Dieu, 44035 Nantes, France
- 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.
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.
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