Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Eenoo, Peter Van; Delbeke, Frans

doi:10.1016/j.jsbmb.2006.06.024

Cited by 107 publications

(128 citation statements)

References 107 publications

(128 reference statements)

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“…Testosterone, epitestosterone, DHT, 5␤-androstane-3␣,17␤-diol, 5␣-androstane-3␣,17␤-diol, and 5␣-androstane-3␤,17␤-diol are also described as metabolites (Schän-zer, 1996;Lévesque and Ayotte, 1999;Uralets and Gillette, 1999;Goudreault et al, 2001;Leder et al, 2001;van de Kerkhof, 2001;Catlin et al, 2002;Stárka, 2003;Van Eenoo and Delbeke, 2006). Although major metabolites in vitro (Lévesque et al, 2002), 6␣-hydroxyandrostenedione and several other hydroxylated steroids are reported as minor metabolites in vivo (Schänzer, 1996;Lévesque and Ayotte, 1999;Goudreault et al, 2001;van de Kerkhof, 2001;Lévesque et al, 2002;Van Eenoo and Delbeke, 2006). Therefore, the 16 metabolites monitored in this study were divided into nonhydroxylated and hydroxylated metabolites (Fig.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Because experimental in vivo human excretion studies are not always approved by an ethics committee, the metabolism of steroids is studied mainly in primary human hepatocyte cultures. However, these in vitro experiments do not always accurately predict the in vivo metabolic profile (Schänzer, 1996;Lévesque and Ayotte, 1999;Uralets and Gillette, 1999;Goudreault et al, 2001;Leder et al, 2001; van de Kerkhof, 2001;Lévesque et al, 2002;Brandon et al, 2003;Van Eenoo and Delbeke, 2006).In this study a chimeric mouse model with functional human hepatocytes was evaluated as an alternative model for metabolic studies (Gonzalez, 2003;Gonzalez and Yu, 2006). Urokinasetype plasminogen activator-severe combined immunodeficiency [uPA(ϩ/ϩ)-SCID] mice have a severe transgene-induced liver disease.…”

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confidence: 99%

“…The complete metabolic profile of AD in chimeric mice after oral AD administration has been investigated. The gas chromatography-mass spectrometry (GC-MS) results are compared with data generated from hepatocyte cell cultures and human administration studies (Schänzer, 1996;Lévesque and Ayotte, 1999;Uralets and Gillette, 1999;Goudreault et al, 2001;Leder et al, 2001;van de Kerkhof, 2001;Lévesque et al, 2002;Brandon et al, 2003;Van Eenoo and Delbeke, 2006).…”

mentioning

confidence: 99%

“…The endogenous anabolic androgenic steroid AD is a precursor of testosterone (Leder et al, 2001;Lévesque et al, 2002;Van Eenoo and Delbeke, 2006) and is prohibited by the World AntiDoping Agency (The 2009 prohibited list, http://www.wada-ama.org/ rtecontent/document/2009_Prohibited_List_ENG_Final_20_Sept_08.pdf). The use of steroids is prohibited in sports because of their performance-enhancing effects.…”

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The uPA(+/+)-SCID Mouse with Humanized Liver as a Model for in Vivo Metabolism of 4-Androstene-3,17-dione

Lootens

Eenoo²,

Meuleman³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The metabolism in primary human hepatocyte cultures often deviates from that in clinical studies, which in turn are hampered by ethical constraints. Here the use of urokinase-type plasminogen activator-severe combined immunodeficiency [uPA(؉/؉)-SCID] mice transplanted with human hepatocytes was investigated as a model for in vivo metabolic studies. The urinary excretion profile after oral administration of 4-androstene-3,17-dione (AD) in chimeric mice was investigated by using gas chromatography-mass spectrometry detection and was compared with previously reported metabolites of AD in humans and cell cultures. Chimeric mice exhibited an AD metabolic profile similar to that of humans, showing androsterone and etiocholanolone as major metabolites. Several hydroxylated steroids were detected as minor metabolites in the chimeric mice compared with hepatocyte cultures. A significant correlation between the extent of liver replacement and the relative abundances of human-type metabolites was established. The results for AD showed that humanized liver uPA-SCID mice can serve as an alternative model for in vivo metabolism studies in humans. In the future, this model could possibly be used for other steroids or pharmaceutical compounds.The liver is one of the most important organs involved in the metabolism of drugs . Most orally administered steroids are metabolized in the liver and excreted in the urine. The misuse of anabolic androgenic steroids in sports is controlled by evaluating the presence of prohibited substances or their metabolites in urine samples. Because experimental in vivo human excretion studies are not always approved by an ethics committee, the metabolism of steroids is studied mainly in primary human hepatocyte cultures. However, these in vitro experiments do not always accurately predict the in vivo metabolic profile (Schänzer, 1996;Lévesque and Ayotte, 1999;Uralets and Gillette, 1999;Goudreault et al., 2001;Leder et al., 2001; van de Kerkhof, 2001;Lévesque et al., 2002;Brandon et al., 2003;Van Eenoo and Delbeke, 2006).In this study a chimeric mouse model with functional human hepatocytes was evaluated as an alternative model for metabolic studies (Gonzalez, 2003;Gonzalez and Yu, 2006). Urokinasetype plasminogen activator-severe combined immunodeficiency [uPA(ϩ/ϩ)-SCID] mice have a severe transgene-induced liver disease. When transplanted with primary human hepatocytes, up to 90% of the diseased liver parenchyma can be replaced with functional hepatocytes of human origin Meuleman et al., 2005). The human albumin (hAlb) concentration, measured in the mouse plasma, is a good marker for the replacement index of the chimeric liver.The expression of human drug-metabolizing enzymes in these chimeric mice has already been investigated (Katoh et al., 2004(Katoh et al., , 2005aTateno et al., 2004;Katoh and Yokoi, 2007;Okumura et al., 2007;Emoto et al., 2008;Muruganandan and Sinal, 2008). Many induction and inhibition reactions typical for human cytochrome P450 enzymes in the liver have been successf...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The uPA(+/+)-SCID Mouse with Humanized Liver as a Model for in Vivo Metabolism of 4-Androstene-3,17-dione

Lootens

Eenoo²,

Meuleman³

et al. 2009

Drug Metab Dispos

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Modern Mass Spectrometry‐Based Analytical Assays

Thevis

2010

Mass Spectrometry in Sports Drug Testing

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Anabolic‐Androgenic Steroids

Barceloux

2012

Medical Toxicology of Drug Abuse

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The use of drugs to enhance physical performance has occurred since the beginning of recorded time. Ancient Greeks ate mushrooms and sesame seeds to enhance performance, and Roman gladiators used stimulants to increase endurance. 1 In modern sports, documentation of the abuse of performance-enhancing drugs appeared in the early 1900s, when athletes ingested stimulants (cocaine, amphetamines, ephedrine, and strychnine) to alleviate fatigue and increase focus. 2 Anabolic-androgenic steroids (AASs) are now the most common illicit drugs used to enhance performance at the modern Olympic Games along with stimulants, primarily by weightlifters and athletes in track and field. 3 The AASs are a group of synthetic derivatives of testosterone with both skeletal muscle-building (anabolic) and masculinizing (androgenic) effects. In 1889, physiologist Charles E. Brown-Sequard reported improvement in a variety of his body functions (strength, intellect, and force of urine stream) following the injection of an extract of testicles from the dog and guinea pig. The primary natural male hormone, testosterone was first isolated from the testis of bulls in 1935 by David et al. 4 Butenandt and Hanisch 5 and Ruzicka et al. 6 independently synthesized testosterone in the same year, and both chemists received the Nobel Prize in 1939 for their work. Most of the AASs were developed during the 1950s when chemists attempted unsuccessfully to separate the anabolic and androgenic properties of these testosterone derivatives. 7 Nandrolone, the 19-nor analog of testosterone was the first anabolic steroid with sufficient dissociation of androgenic and anabolic properties to justify introduction into clinical practice during the 1950s. 8 Dr. John Ziegler, an American physician-weightlifter, administered AASs to 3 future American weightlifting champions after learning of the success of AAS-using Russian weightlifters at the 1954 World Championships. 9 In 1958, the US Food and Drug Administration (FDA) approved the use of methandrostenolone (Dianabol) for the treatment of hypogonadism, resulting in the increased availability of this steroid. By the mid-1960s, the use of AASs to Contents lists available at SciVerse ScienceDirect

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Metabolism and excretion of anabolic steroids in doping control—New steroids and new insights

Cited by 107 publications

References 107 publications

The uPA(+/+)-SCID Mouse with Humanized Liver as a Model for in Vivo Metabolism of 4-Androstene-3,17-dione

The uPA(+/+)-SCID Mouse with Humanized Liver as a Model for in Vivo Metabolism of 4-Androstene-3,17-dione

Modern Mass Spectrometry‐Based Analytical Assays

Anabolic‐Androgenic Steroids

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