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Erythropoietin gene doping: facts and fictions

Erythropoietin-Gen Doping: Fakten und Fiktionen

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Abstract

The substances and methods forbidden to increase the mass of hemoglobin (Hb) in sports (“blood doping”) include red blood cell (RBC) transfusion, Hb infusion, recombinant or chemical agents that stimulate the erythropoietin receptor, erythropoietin gene (EPO) transfer, and misuse of drugs activating endogenous EPO expression. The two latter possibilities are considered in this article. EPO transgenes have been explored in animal studies and in seminal human trials. However, the method is still not well engineered, despite almost 10 years of clinical studies. The menacing detriment of EPO transfer is immunogenicity of the transgenic DNA or cells and of the secreted recombinant proteins, respectively. However, since chemicals are available that activate EPO-controlling transcription factors, these compounds may also be misused in sports. The chemicals include inhibitors of GATA, which prevent GATA-2 from suppressing the EPO promoter, and stabilizers of the hypoxia-inducible transcription factors (HIFs), which activate the EPO enhancer. While there is a hope that EPO transfer has not yet entered the sports scene as a means of blood doping, drugs that increase endogenous EPO expression must be considered as a realistic threat with regard to doping efforts. In particular, there is suspicion that cobaltous salt, which is a potent stimulator of EPO when taken orally, could be misused by athletes.

Zusammenfassung

Die im Sport verbotenen Substanzen und Methoden zur Erhöhung der Hämoglobinmasse (“Blutdoping”) beinhalten Erythrozytentransfusionen, Hämoglobininfusionen, den Erythropoietinrezeptor aktivierende rekombinante oder chemische Arzneistoffe, den Transfer des Erythropoietingens (EPO) und EPO aktivierende Substanzen. Letztere zwei Methoden werden hier betrachtet. Der EPO-Transfer wurde bereits in Tierversuchen und ersten klinischen Studien erprobt, ist jedoch medizinisch nicht ausgereift. Vorrangiges Problem ist die Immunogenität der transgenen DNA bzw. Zellen und der rekombinanten Proteine. Es gibt jedoch kleinmolekulare Stoffe, welche auf die Transkriptionsfaktoren einwirken, die das endogene EPO kontrollieren. Da diese Chemikalien leicht erhältlich sind und oral eingenommen werden können, besteht die Gefahr, dass sie im Sport angewendet werden. Zu solchen Substanzen gehören Antagonisten von GATA, die den EPO-Promotor de-blockieren, und Stabilisatoren der Hypoxie induzierbaren Transkriptionsfaktoren (HIF), die den EPO-Enhancer aktivieren. Während die Hoffnung besteht, dass der direkte EPO-Transfer noch keinen Eingang in die Sportszene gefunden hat, stellen die chemischen Stoffe, die EPO induzieren, eine reale Gefahr dar. Dies gilt insbesondere für Kobaltsalze, die oral eingenommen werden können.

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  1. Institute of Physiology, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany

    Wolfgang Jelkmann M.D.

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  1. Wolfgang Jelkmann
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Correspondence to Wolfgang Jelkmann M.D..

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Jelkmann, W., Jelkmann, W. Erythropoietin gene doping: facts and fictions. Sportwiss 42, 280–285 (2012). https://doi.org/10.1007/s12662-012-0268-2

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