Erythropoietin

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erythropoietin
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Erythropoietin (

hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO (around 10 mU/mL) are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any anemia, and hypoxemia
due to chronic lung disease and mouth disease.

Erythropoietin is produced by interstitial

proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood. It is homologous with thrombopoietin
.

venous thromboembolism
, and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided.

rhEPO has been used illicitly as a

posttranslational modification
.

Pharmacology

EPO is highly glycosylated (40% of total molecular weight), with half-life in blood around 5 h. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections).

Function

Red blood cell production

Erythropoietin is an essential hormone for red blood cell production. Without it, definitive

erythroblast and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells from apoptosis
, or cell death.

Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g.,

erythroid lineage from multipotent progenitors. The burst-forming unit-erythroid (BFU-E) cells start erythropoietin receptor expression and are sensitive to erythropoietin. Subsequent stage, the colony-forming unit-erythroid (CFU-E
), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.

Nonhematopoietic roles

Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including vasoconstriction-dependent hypertension, stimulating angiogenesis, and promoting cell survival via activation of EPO receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal is controversial with numerous studies showing no effect.[5] It is also inconsistent with the low levels of EPO receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.[6]

Mechanism of action

Erythropoietin has been shown to exert its effects by

binding to the erythropoietin receptor (EpoR).[7][8] EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signalling cascade. This initiates the STAT5, PIK3 and Ras MAPK pathways. This results in differentiation, survival and proliferation of the erythroid cell.[9] SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.[10]

High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies.[11] In controlled experiments, a functional EPO receptor is not detected in those tissues.[12] In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis.[13] In addition, there is conclusive evidence that EPO receptor expression is upregulated in brain injury.[14]

Synthesis and regulation

Erythropoietin levels in blood are quite low in the absence of anemia, at around 10 mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10 000 mU/mL of blood. In adults, EPO is synthesized mainly by interstitial cells in the peritubular capillary bed of the

hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia GATA2 inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production.[20]

Erythropoietin production can be induced by HIF-2α as well as by PGC-1α.[21] Erythropoietin also activates these factors, resulting in a positive feedback loop.[21]

Medical use

Main article: Erythropoiesis-stimulating agent

Erythropoietins available for use as

package inserts include boxed warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 g/dL to 12 g/dL.[24]

History

In 1905, Paul Carnot proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to bloodletting, Carnot and his graduate student Clotilde-Camille Deflandre[25] attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was purified and confirmed as erythropoietin.[19][26]

In 1977, Goldwasser and Kung purified EPO.

Epogen for use in certain anemias.[30][31]

Gregg L. Semenza and Peter J. Ratcliffe studied the EPO gene and its oxygen-dependent regulation. Along with William Kaelin Jr., they were awarded the 2019 Nobel Prize in Physiology or Medicine for their discovery of hypoxia-inducible factor (HIF), which regulates the EPO gene, as well as other genes, in response to hypoxia.[32]

Biosimilars

See also:
Biosimilars

In December 2007, Retacrit and Silapo (both

epoetin zeta) were approved for use in the European Union.[33][34]

Usage as doping product

As a performance-enhancing drug, EPO has been banned since the early 1990s, but a first test was not available until the 2000 Summer Olympics.[35] Before this test was available, some athletes were sanctioned after confessing to having used EPO, for example in the Festina affair, when a car with doping products for the Festina cycling team was found.

The first doping test in cycling was used in the 2001 La Flèche Wallonne. The first rider to test positive in that race was Bo Hamburger, although he was later acquitted because his B-sample was not conclusive.[36]

The U.S. Postal Service Pro Cycling Team, under the leadership of Lance Armstrong and Johan Bruyneel, ran a sophisticated doping program that lasted for many years during the late 1990s and early 2000s. Erythropoietin was a common substance used by the cyclists.[37]

A 2007 study showed that EPO has a significant effect on exercise performance.[clarify][38] A 2017 study showed at submaximal exertion the effects of EPO were not distinguishable from a placebo. Stating "[At] Submaximal [exertion]...[mean power] did not differ between groups." Nevertheless, at "maximal [exertion power output was] higher in the rHuEPO group compared with the placebo group." So, even though there was no difference at lower levels of exertion at maximal exertion the EPO group still performed better than the placebo group.[39]

In March 2019, American mixed martial artist and former

USADA, and was stripped of the UFC bantamweight title and suspended for 2 years.[40] In September 2023 two-time tennis major champion Simona Halep received a 4-year suspension by the International Tennis Integrity Agency for two separate violations, one concerning the level of EPO in a blood sample collected in August 2022; Halep maintained her innocence, and indicated she would appeal the ban.[41]

EPO has been used as a performance enhancing agent in horse racing since at least 2019.[42]

References

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  2. ^ "Erythropoietin". Dictionary.com Unabridged (Online). n.d.
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  24. ^ "Safety Labeling Changes: Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa)". MedWatch: The FDA Safety Information and Adverse Event Reporting Program. United States Food and Drug Administration. 11 August 2011. Archived from the original on 12 January 2017. Retrieved 16 December 2019.
  25. ^ Carnot P, Deflandre C (1906). "Sur l'activite hematopoietique du serum au cours de la regeneration du sang". Compt. Rend. Acad. Sci. 143: 384–386.
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  32. ^ "The Nobel Prize in Physiology or Medicine 2019". NobelPrize.org. 7 October 2019. Archived from the original on 31 October 2021. Retrieved 30 October 2019.
  33. ^ "Retacrit EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 30 December 2019. Retrieved 2 April 2020.
  34. ^ "Silapo EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 22 October 2020. Retrieved 2 April 2020.
  35. ^ "EPO DETECTION". World Anti-Doping Agency. December 2014. Archived from the original on 7 September 2017. Retrieved 17 December 2017.
  36. ^ "Hamburger cleared of EPO use". BBC. 10 August 2001. Archived from the original on 16 April 2016. Retrieved 17 December 2017.
  37. ^ Perishable (10 October 2012). "Statement From USADA CEO Travis T. Tygart Regarding The U.S. Postal Service Pro Cycling Team Doping Conspiracy | U.S. Anti-Doping Agency (USADA)". www.usada.org. Archived from the original on 26 August 2021. Retrieved 26 August 2021.
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  41. ^ "Simona Halep: Will appeal 4-year ban over doping violations", ESPN, September 12, 2023
  42. ^ Munson, Emilie (6 February 2022). "N.Y. lab losing battle of doping in horse racing's 'cat and mouse game'". www.timesunion.com. Archived from the original on 6 February 2022. Retrieved 7 February 2022.

Further reading

External links