Combined chemical and biotechnological production of 20βOH-NorDHCMT, a long-term metabolite of Oral-Turinabol (DHCMT)

Liu, Jiaxin; Chen, Lei; Joseph, Jan Felix; Naß, Alexandra; Stoll, Anna; Torre, Xavier de la; Botrè, Francesco; Wolber, Gerhard; Parr, Maria Kristina; Bureik, Matthias

doi:10.1016/j.jinorgbio.2018.02.020

Cited by 20 publications

(21 citation statements)

References 31 publications

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“…Subsequent to metabolite detection, full characterization of new target analytes is required, preferably by chemical synthesis and comparison of the synthetic products with metabolites observed in elimination study urine samples. Such syntheses and characterization studies were accomplished by Liu et al and Forsdahl et al concerning long‐term metabolites of dehydrochloromethyltestosterone. Especially the metabolite characterized as 4α‐chloro‐18‐nor‐17β‐hydroxymethyl‐17α‐methyl‐5α‐androst‐13‐en‐3a‐ol (M3) has been shown to offer utmost retrospectivity concerning the administration of dehydrochloromethyltestosterone and methylclostebol, contributing to significant prolongations of detection windows.…”

Section: Anabolic Agentsmentioning

confidence: 99%

Annual banned‐substance review: Analytical approaches in human sports drug testing

Thevis

Kuuranne

Geyer

2019

Drug Testing and Analysis

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A number of high profile revelations concerning anti‐doping rule violations over the past 12 months have outlined the importance of tackling prevailing challenges and reducing the limitations of the current anti‐doping system. At this time, the necessity to enhance, expand, and improve analytical test methods in response to the substances outlined in the World Anti‐Doping Agency (WADA) Prohibited List represents an increasingly crucial task for modern sports drug testing programs. The ability to improve analytical testing methods often relies on the expedient application of novel information regarding superior target analytes for sports drug testing assays, drug elimination profiles, and alternative sample matrices, together with recent advances in instrumental developments. This annual banned‐substance review evaluates literature published between October 2017 and September 2018 offering an in‐depth evaluation of developments in these arenas and their potential application to substances reported in WADA's 2018 Prohibited List.

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Section: Anabolic Agentsmentioning

confidence: 99%

Annual banned‐substance review: Analytical approaches in human sports drug testing

Thevis

Kuuranne

Geyer

2019

Drug Testing and Analysis

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“…A critical difference is that DHCMT M3 comprises a saturated A‐ring, while the described metandienone metabolites and DHCMT as well as the published metabolite 4‐chloro‐17β‐hydroxymethyl‐17α‐methyl‐18‐norandrosta‐1,4,13‐trien‐3‐one feature unsaturated A‐ring systems. Furthermore, the deduction that a loss of 103 Da from the molecular ion must be reflected by an equivalently increasing abundance of m/z 103 in the mass spectrum of saturated structural analogs, is not substantiated by any experimental data nor verified by the cited or also later published material . EI fragmentation produces a charged and a non‐charged fragment.…”

mentioning

confidence: 93%

“…Furthermore, the deduction that a loss of 103 Da from the molecular ion must be reflected by an equivalently increasing abundance of m/z 103 in the mass spectrum of saturated structural analogs, is not substantiated by any experimental data nor verified by the cited 3 or also later published material. 4 EI fragmentation produces a charged and a non-charged fragment. Only the charged fragment (ions) can be detected in the MS; neutral molecules and radicals do not appear as peaks in the mass spectrum.…”

mentioning

confidence: 99%

Response to letter to the editor: “Comments on Unambiguous identification and characterization of a long‐term human metabolite of dehydrochloromethyltestosterone”

Forsdahl

Geisendorfer

Göschl

et al. 2018

Drug Testing and Analysis

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“…This regio-and stereospecific oxy functionalization is of high biological relevance, and especially CYPs involved in steroid biosynthesis have been considered to be unable to metabolize xenobiotics. In the last decade, this hypothesis, however, was demonstrated to be not correct (6)(7)(8)(9)(10). Still, strict structural requirements for substrates have been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Corticosteroid Biosynthesis Revisited: No Direct Hydroxylation of Pregnenolone by Steroid 21-Hydroxylase

et al. 2021

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Cytochrome P450s (CYPs) are an essential family of enzymes in the human body. They play a crucial role in metabolism, especially in human steroid biosynthesis. Reactions catalyzed by these enzymes are highly stereo- and regio-specific. Lack or severe malfunctions of CYPs can cause severe diseases and even shorten life. Hence, investigations on metabolic reactions and structural requirements of substrates are crucial to gain further knowledge on the relevance of different enzymes in the human body functions and the origin of diseases. One key enzyme in the biosynthesis of gluco- and mineralocorticoids is CYP21A2, also known as steroid 21-hydroxylase. To investigate the steric and regional requirements of substrates for this enzyme, we performed whole-cell biotransformation assays using a strain of fission yeast Schizosaccharomyces pombe recombinantly expressing CYP21A2. The progestogens progesterone, pregnenolone, and their 17α-hydroxy-derivatives were used as substrates. After incubation, samples were analyzed using gas chromatography coupled to mass spectrometry. For progesterone and 17α-hydroxyprogesterone, their corresponding 21-hydroxylated metabolites 11-deoxycorticosterone and 11-deoxycortisol were detected, while after incubation of pregnenolone and 17α-hydroxypregnenolone, no hydroxylated product was observed. Findings were confirmed with authentic reference material. Molecular docking experiments agree with these results and suggest that interaction between the 3-oxo group and arginine-234 of the enzyme is a strict requirement. The presented results demonstrate once more that the presence of an oxo-group in position 3 of the steroid is indispensable, while a 3-hydroxy group prevents hydroxylation in position C-21 by CYP21A2. This knowledge may be transferred to other CYP21A2 substrates and hence help to gain essential insights into steroid metabolism.

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Combined chemical and biotechnological production of 20βOH-NorDHCMT, a long-term metabolite of Oral-Turinabol (DHCMT)

Cited by 20 publications

References 31 publications

Annual banned‐substance review: Analytical approaches in human sports drug testing

Annual banned‐substance review: Analytical approaches in human sports drug testing

Response to letter to the editor: “Comments on Unambiguous identification and characterization of a long‐term human metabolite of dehydrochloromethyltestosterone”

Corticosteroid Biosynthesis Revisited: No Direct Hydroxylation of Pregnenolone by Steroid 21-Hydroxylase

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