Parr, Maria Kristina ORCID: 0000-0001-7407-8300, Zoellner, Andy, Fusshoeller, Gregor, Opfermann, Georg, Schloerer, Nils ORCID: 0000-0002-0990-9582, Zorio, Mirela, Bureik, Matthias ORCID: 0000-0002-9515-6248 and Schaenzer, Wilhelm (2012). Unexpected contribution of cytochrome P450 enzymes CYP11B2 and CYP21, as well as CYP3A4 in xenobiotic androgen elimination - Insights from metandienone metabolism. Toxicol. Lett., 213 (3). S. 381 - 392. CLARE: ELSEVIER IRELAND LTD. ISSN 1879-3169

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Abstract

The metabolism of a variety of anabolic steroids frequently misused for doping purposes has been investigated in the last years. This research mainly focused on main and long-term metabolites suitable for detection, but detailed clearance mechanisms have rarely been elucidated. Recent studies on metandienone focused on the identification of 17 beta-hydroxymethyl-17 alpha-methyl-18-norandrosta-1,4,13-trien-3-one (20 beta OH-NorMD) as long-term metabolite, however, the metabolic pathway of its generation remained unclear. Metandienone and its Wagner-Meerwein rearrangement product 17,17-dimethyl-18-norandrosta-1,4,13- trien-3-one (NorMD) were hydroxylated by different human cytochrome P450 enzymes (CYPs). Some of their hydroxylation products were chemically synthesized and characterized by mass spectrometry to allow for their trace detection in urine samples. Following oral administration of metandienone or NorMD in one human volunteer each the post administration urines were checked for the presence of those hydroxylated metabolites using GC-MS/MS analysis. The human mitochondrial steroid hydroxylating enzymes CYP11B1 and CYP11B2 were capable to metabolize metandienone leading to the formation of 11 beta-hydroxymetandienone and 18-hydroxymetandienone. Following Wagner-Meerwein rearrangement, the resulting products could be assigned to 20 beta OH-NorMD and 11 beta OH-NorMD. The contribution of CYP11B1 and CYP11B2 in human metabolism of metandienone was confirmed by analysis of post-administration samples of metandienone and NorMD. Combined with the results from a previous study, enzymatic pathways were identified that involve CYP21 and CYP3A4 in the hydroxylation of NorMD, while CYP21, CYP3A4 and CYP11B2 take part in 20 beta OH-NorMD generation from MD. The current study represents a valuable contribution to the elucidation of clearance mechanisms of anabolic steroids and also indicates that mainly non-liver CYPs seem to be involved in these processes (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Parr, Maria KristinaUNSPECIFIEDorcid.org/0000-0001-7407-8300UNSPECIFIED
Zoellner, AndyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fusshoeller, GregorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Opfermann, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schloerer, NilsUNSPECIFIEDorcid.org/0000-0002-0990-9582UNSPECIFIED
Zorio, MirelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bureik, MatthiasUNSPECIFIEDorcid.org/0000-0002-9515-6248UNSPECIFIED
Schaenzer, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-482915
DOI: 10.1016/j.toxlet.2012.07.020
Journal or Publication Title: Toxicol. Lett.
Volume: 213
Number: 3
Page Range: S. 381 - 392
Date: 2012
Publisher: ELSEVIER IRELAND LTD
Place of Publication: CLARE
ISSN: 1879-3169
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MASS-SPECTROMETRIC IDENTIFICATION; ANABOLIC-STEROIDS; ESCHERICHIA-COLI; FUNCTIONAL-CHARACTERIZATION; URINARY METABOLITES; FISSION YEAST; EXPRESSION; MECHANISM; ADRENODOXIN; STANOZOLOLMultiple languages
ToxicologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48291

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