CYP21-catalyzed production of the long-term urinary metandienone metabolite 17β-hydroxymethyl-17α-methyl-18-norandrosta-1,4,13-trien-3-one: a contribution to the fight against doping

2010 ◽  
Vol 391 (1) ◽  
Author(s):  
Andy Zöllner ◽  
Maria Kristina Parr ◽  
Călin-Aurel Drăgan ◽  
Stefan Dräs ◽  
Nils Schlörer ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Reference Material ◽  
Anabolic Androgenic Steroids ◽  
Reference Substance ◽  
Cytochrome P450 Enzymes ◽  
Whole Cell ◽  
In Doping ◽  
Whole Cell Biotransformation ◽  
Androgenic Steroids

AbstractAnabolic-androgenic steroids are some of the most frequently misused drugs in human sports. Recently, a previously unknown urinary metabolite of metandienone, 17β-hydroxymethyl-17α-methyl-18-norandrosta-1,4,13-trien-3-one (20OH-NorMD), was discovered via LC-MS/MS and GC-MS. This metabolite was reported to be detected in urine samples up to 19 days after administration of metandienone. However, so far it was not possible to obtain purified reference material of this metabolite and to confirm its structure via NMR. Eleven recombinant strains of the fission yeastSchizosaccharomyces pombethat express different human hepatic or steroidogenic cytochrome P450 enzymes were screened for production of this metabolite in a whole-cell biotransformation reaction. 17,17-Dimethyl-18-norandrosta-1,4,13-trien-3-one, chemically derived from metandienone, was used as substrate for the bioconversion, because it could be converted to the final product in a single hydroxylation step. The obtained results demonstrate that CYP21 and to a lesser extent also CYP3A4 expressing strains can catalyze this steroid hydroxylation. Subsequent 5 l-scale fermentation resulted in the production and purification of 10 mg of metabolite and its unequivocal structure determination via NMR. The synthesis of this urinary metandienone metabolite viaS. pombe-based whole-cell biotransformation now allows its use as a reference substance in doping control assays.

scholarly journals Doping Practices in International Weightlifting: Analysis of sanctioned athletes/support personnel from 2008-2019 and retesting of samples from the 2008 and 2012 Olympic Games

2020 ◽  
Author(s):  
Alexander Kolliari-Turner ◽  
Brian Oliver ◽  
Giscard Lima ◽  
John P. Mills ◽  
Guan Wang ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Regional Differences ◽  
Olympic Games ◽  
Anabolic Androgenic Steroids ◽  
Sample Storage ◽  
Support Personnel ◽  
In Doping ◽  
Targeted Testing ◽  
Androgenic Steroids

Abstract Background The pervasiveness of doping and findings of anti-doping corruption threaten weightlifting’s position at the 2024 Olympics. Analysing the practices of doping weightlifters could identify patterns in doping that assist in future detection.Methods We analysed publicly available data on sanctioned athletes/support personnel from the International Weightlifting Federation (IWF) between 2008–2019 and retrospective Anti-Doping Rule Violations (ADRVs) from the 2008 and 2012 Olympics.Results There were 565 sanctions between 2008–2019 of which 82% related to exogenous and endogenous Anabolic Androgenic Steroids (AAS). The distribution of exogenous AAS, endogenous AAS and other detected substances varied by IWF Continental Federation (p ≤ 0.05) with Europe (74%, 11%, 15%) and Asia (70%, 15%, 15%) showing a higher detection of exogenous AAS compared to Pan America (37%, 30%, 33%) and Africa (50%, 17%, 33%). When looking at the 10 most detected substances, the nations with the highest number of sanctions (range 17–35) all had at least one overrepresented substance that accounted for 38–60% of all detected substances. The targeted re-analysis of samples from the 2008 and 2012 Olympics due to the discovery of long-term metabolites for exogenous AAS has to date produced 61 retrospective ADRVs in weightlifting. Of these, 34 were original medallists (9 Gold, 10 Silver and 15 Bronze), the highest of any sport. The exogenous AAS Dehydrochloromethyltestosterone and Stanozolol accounted for 83% of detected substances and were present in 95% of these samples.Conclusion Based on these findings of regional differences in doping practices, weightlifting would benefit from the targeted testing of certain regions and continuing investment in long-term sample storage as the sensitivity and specificity of detection continues to improve.

scholarly journals Doping Practices in International Weightlifting: Analysis of sanctioned athletes/support personnel from 2008-2019 and retesting of samples from the 2008 and 2012 Olympic Games

2020 ◽  
Author(s):  
Alexander Kolliari-Turner ◽  
Brian Oliver ◽  
Giscard Lima ◽  
John P. Mills ◽  
Guan Wang ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Regional Differences ◽  
Olympic Games ◽  
Anabolic Androgenic Steroids ◽  
Sample Storage ◽  
Support Personnel ◽  
In Doping ◽  
Targeted Testing ◽  
Androgenic Steroids

Abstract Background: The pervasiveness of doping and findings of anti-doping corruption threaten weightlifting’s position at the 2024 Olympic Games. Analysing the practices of doping in weightlifters could identify patterns in doping that assist in future detection. Methods: We analysed publicly available data on sanctioned athletes/support personnel from the International Weightlifting Federation between 2008-2019 and announced retrospective Anti-Doping Rule Violations (ADRVs) from the 2008 and 2012 Olympic Games. Results: There were 565 sanctions between 2008-2019 of which 82% related to the detection of exogenous Anabolic Androgenic Steroids (AAS) metabolites and markers indicating endogenous AAS usage. The detection of exogenous AAS metabolites, markers of endogenous AAS usage and other substance metabolites varied by IWF Continental Federation (p ≤ 0.05) with Europe (74%, 11%, 15%) and Asia (70%, 15%, 15%) showing a higher detection of exogenous AAS compared to Pan America (37%, 30%, 33%) and Africa (50%, 17%, 33%). When looking at the 10 most detected substances, the nations with the highest number of sanctions (range 17-35) all had at least one overrepresented substance that accounted for 38-60% of all detected substances. The targeted re-analysis of samples from the 2008 and 2012 Olympic Games due to the discovery of long-term metabolites for exogenous AAS resulted in 61 weightlifters producing retrospective ADRVs. This includes 34 original medallists (9 Gold, 10 Silver and 15 Bronze), the highest of any sport identified by Olympic Games sample re-testing. The exogenous AAS Dehydrochloromethyltestosterone and Stanozolol accounted for 83% of detected substances and were present in 95% of these samples. Conclusion: Based on these findings of regional differences in doping practices, weightlifting would benefit from the targeted testing of certain regions and continuing investment in long-term sample storage as the sensitivity and specificity of detection continues to improve.

scholarly journals Evaluation of Pharmacogenomics Testing of Cytochrome P450 Enzymes in the Military Health System From 2015 to 2020

2021 ◽  
Vol 187 (Supplement_1) ◽  
pp. 1-8
Author(s):  
Elaine D Por ◽  
Daniel J Selig ◽  
Geoffrey C Chin ◽  
Jesse P DeLuca ◽  
Thomas G Oliver ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Health System ◽  
Point Of Care ◽  
Cytochrome P450 Enzymes ◽  
Military Health System ◽  
Military Health ◽  
Patient Demographics ◽  
The Military ◽  
The Relationship

ABSTRACT Pharmacogenomics (PGx) plays a fundamental role in personalized medicine, providing an evidence-based treatment approach centered on the relationship between genomic variations and their effect on drug metabolism. Cytochrome P450 (CYP450) enzymes are responsible for the metabolism of most clinically prescribed drugs and a major source of variability in drug pharmacokinetics and pharmacodynamics. To assess the prevalence of PGx testing within the Military Health System (MHS), testing of specific CYP450 enzymes was evaluated. Data were retrospectively obtained from the Military Health System Management Analysis and Reporting Tool (M2) database. Patient demographics were identified for each test, along with TRICARE status, military treatment facility, clinic, and National Provider Identifier. A total of 929 patients received 1,833 PGx tests, predominantly composed of active duty/guard service members (N = 460; 49.5%), with highest testing rates in the army (51.5%). An even distribution in testing was observed among gender, with the highest rates in Caucasians (41.7%). Of the CYP enzymes assessed, CYP2C19 and CYP2D6 accounted for 87.8% of all PGx CYP testing. The majority of patients were tested in psychiatry clinics (N = 496; 53.4%) and primary care clinics (N = 233; 25.1%), accounting for 56.4% and 24.8% of all tests, respectively. Testing was found to be provider driven, suggesting a lack of a standardized approach to PGx and its application in patient care within the MHS. We initially recommend targeted education and revising testing labels to be more uniform and informative. Long-term recommendations include establishing pharmacy-driven protocols and point-of-care PGx testing to optimize patient outcomes.

scholarly journals Effects in Rats of Maternal Exposure to Raspberry Leaf and Its Constituents on the Activity of Cytochrome P450 Enzymes in the Offspring

2010 ◽  
Vol 30 (2) ◽  
pp. 216-224 ◽  
Author(s):  
Emilija Makaji ◽  
Shirley H. Y. Ho ◽  
Alison C. Holloway ◽  
Denis J. Crankshaw
Keyword(s):  
Cytochrome P450 ◽  
Female Offspring ◽  
Maternal Exposure ◽  
Female Rats ◽  
Cytochrome P450 Enzymes ◽  
Fluorogenic Substrates ◽  
Hepatic Microsomes ◽  
Maternal Consumption ◽  
Nulliparous Female

The goal of our study was to determine whether maternal exposure to red raspberry leaf (RRL) and its constituents can permanently alter biotransformation of fluorogenic substrates by cytochrome P450 (CYP) in the livers of male and female offspring. Nulliparous female rats received vehicle, raspberry leaf, kaempferol, quercetin, or ellagic acid orally once breeding had been confirmed until parturition. Hepatic microsomes were prepared from animals at birth (postnatal day 1 [PND1]), weaning (PND21), PND65, and PND120 to determine the biotransformation of 8 fluorogenic substrates. The pattern of biotransformation of all but 2 of the substrates was gender specific. Maternal consumption of RRL increased biotransformation of 3 substrates by female offspring at PND120 resulting in a more masculine profile. Kaempferol and quercetin had a similar effect to RRL. These results suggest that maternal consumption of either RRL or some of its constituents leads to long-term alterations of CYP activity in female offspring.

P2545Long-term use of anabolic-androgenic steroids in male weightlifters is associated with left ventricular systolic dysfunction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Abdullah ◽  
A Bjornebekk ◽  
L Dejgaard ◽  
L Hauger ◽  
T Edvardsen ◽  
...  
Keyword(s):  
Left Ventricular Mass ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Anabolic Androgenic Steroids ◽  
Ventricular Systolic Function ◽  
Ventricular Mass ◽  
Androgenic Steroids

Abstract Background Illicit use of anabolic-androgenic steroids (AAS) is widespread and has adverse psychological and cardiovascular effects. Few well-powered studies have explored the effect of long-term AAS-use on left ventricular systolic function. Purpose To explore the relationship between long-term use of AAS and left ventricular mass and systolic function. Methods We included male weightlifters with a history of >1 year of cumulative AAS-use and male weightlifters unexposed to AAS. We performed echocardiography in all and assessed left ventricular mass using 2D echocardiographic linear measurements and Cube formula, left ventricular ejection fraction (EF) ad modum Simpson, and left ventricular global longitudinal strain (GLS) by speckle-tracking echocardiography. Results We recruited 100 male weightlifters, 58 of whom were previous or current AAS-users with mean±SD AAS-use of 10.4±7.0 years, and 42 unexposed weightlifters. There were no difference in age (35.5±9.2 vs. 35.3±7.5 years, p=0.8) nor body mass index (BMI) (BMI 31.4±5.0 vs. 30.1±3.5, p=0.6) between AAS-exposed and unexposed weightlifters. Compared with unexposed weightlifters, AAS-exposed weightlifters demonstrated thicker interventricular septum (11.2±2.4 vs. 9.2±1.3 mm, p<0.001), thicker left ventricular posterior wall dimension (10.1±2.1 vs. 8.9±1.3 mm, p<0.001), and higher left ventricular mass index (99.7±25.4 vs. 78.4±12.1 g/m2, p<0.001). Both left ventricular EF and left ventricular GLS were decreased in AAS-exposed weightlifters compared with unexposed weightlifters (49±9 vs. 53±6%, p=0.02, and −15.6±2.6 vs. −18.3±2.1%, p<0.001) (Figure). Conclusion AAS use in male weightlifters was associated with increased left ventricular mass and impaired left ventricular systolic function. Our results suggest considerable adverse cardiac effects of AAS use, but the results need confirmation in prospective observational trials.

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