Putkaradze, Natalia, Hartz, Philip ORCID: 0000-0003-0390-3486, Hutter, Michael C., Zapp, Josef, Thevis, Mario and Bernhardt, Rita (2021). Metabolism of oral turinabol by the human brain cholesterol 24-hydroxylase CYP46A1. J. Steroid Biochem. Mol. Biol., 212. OXFORD: PERGAMON-ELSEVIER SCIENCE LTD. ISSN 1879-1220

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Abstract

The human microsomal cytochrome P450 enzyme CYP46A1 plays a crucial role in cholesterol elimination from the brain. It performs a 24-hydroxylation of cholesterol and is of outstanding significance for memory and cognition. This study demonstrates the catalytic activity of human CYP46A1 towards an anabolic androgenic steroid, oral turinabol (dehydrochloromethyltestosterone, 4-chloro-17 beta-dihydroxy,17 alpha-methylandrosta-1,4-dien-3-one), which is a doping substance. CYP46A1 is the first human microsomal steroid-converting P450 showing activity towards this xenobiotic compound. Furthermore, the inhibitory effect of oral turinabol on the cholesterol conversion has been investigated in vitro demonstrating competition of the two substrates on the active site of CYP46A1 which might be of importance for potential pathogenic effects of oral turinabol. The conversion of oral turinabol was found to be selective resulting in the formation of only one product, as shown by HPLC analysis. To produce sufficient amounts of this product for NMR analysis, a system expressing human full-length CYP46A1 and CPR on a bicistronic vector was successfully developed realizing the selective cholesterol 24-hydroxylation in E. coli in mg amounts. Using this novel whole-cell system, the conversion of oral turinabol was performed and the product of this conversion by CYP46A1 was isolated and identified as 16 beta-hydroxy oral turinabol by NMR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Putkaradze, NataliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartz, PhilipUNSPECIFIEDorcid.org/0000-0003-0390-3486UNSPECIFIED
Hutter, Michael C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zapp, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thevis, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernhardt, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-584442
DOI: 10.1016/j.jsbmb.2021.105927
Journal or Publication Title: J. Steroid Biochem. Mol. Biol.
Volume: 212
Date: 2021
Publisher: PERGAMON-ELSEVIER SCIENCE LTD
Place of Publication: OXFORD
ISSN: 1879-1220
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HUMAN CYTOCHROME-P450 46A1; EXPRESSION; MECHANISM; TURNOVER; BINDING; ROLESMultiple languages
Biochemistry & Molecular Biology; Endocrinology & MetabolismMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58444

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