Enzyme-assisted synthesis and structure characterization of glucuronide conjugates of methyltestosterone (17 alpha-methylandrost-4-en-17 beta-ol-3-one) and nandrolone (estr-4-en-17 beta-ol-3-one) metabolites.

Détails

ID Serval
serval:BIB_10446C0FF7F6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Enzyme-assisted synthesis and structure characterization of glucuronide conjugates of methyltestosterone (17 alpha-methylandrost-4-en-17 beta-ol-3-one) and nandrolone (estr-4-en-17 beta-ol-3-one) metabolites.
Périodique
Bioconjugate chemistry
Auteur⸱e⸱s
Kuuranne T., Aitio O., Vahermo M., Elovaara E., Kostiainen R.
ISSN
1043-1802 (Print)
ISSN-L
1043-1802
Statut éditorial
Publié
Date de publication
2002
Peer-reviewed
Oui
Volume
13
Numéro
2
Pages
194-199
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
A new and useful method based on enzyme-assisted synthesis was developed for producing 3 alpha-O-beta-D-glucuronide conjugates from synthetic phase I metabolites of methyltestosterone and nandrolone. The formed glucuronide conjugates of 17 alpha-methyl-5 alpha-androstane-3 alpha,17 beta-diol (I), 17 alpha-methyl-5 beta-androstane-3 alpha,17 beta-diol (II), 5 alpha-estran-3 alpha-ol-17-one (III), and 5 beta-estran-3 alpha-ol-17-one (IV) are urinary metabolites, indicating the human misuse of the above-mentioned anabolic androgenic steroids (AAS). The common lack of reference material precludes the use and validation of these biomarkers in human doping control. Liver microsomes from Aroclor 1254-induced rats were used as a highly active source of mammalian UDP-glucuronosyltransferases (UGT, EC 2.4.1.17). After purification by protein precipitation, liquid-liquid extraction (dichloromethane), C-18 solid-phase extraction, and lyophilization, the steroid glucuronide structures were characterized by (1)H and (13)C NMR spectroscopy and tandem mass spectrometry. The enzymatic method was highly stereoselective, producing a single major conjugate from the parent steroids I-IV. The stereochemically pure steroid glucuronide conjugates were recovered in milligram amounts (1.0-2.8 mg, yield 12-29%), which is sufficient for veterinary and human doping control analyses; for pharmaco-, toxico-, and enzyme kinetic studies in the pharmaceutical industry; for clinical laboratories; and for forensic medicine. A new sensitive LC-MS method was developed for controlling the product purity in syntheses, as well as for enzyme kinetic characterization of AAS-metabolizing UGT activities in rat liver toward the aglycones I-IV. In this study, the UGT enzymes responsible for the formation of 3 alpha-O-linked glucuronides from the substrates I, II, III, and IV exhibited the specific enzyme activity values: 25, 124, 48, and 212 nmol/mg microsomal protein in a 2-h incubation, respectively.

Mots-clé
Animals, Biotransformation, Female, Glucuronides/biosynthesis, Glucuronides/chemistry, Glucuronides/metabolism, Humans, Kinetics, Magnetic Resonance Spectroscopy, Mass Spectrometry, Methyltestosterone/analogs & derivatives, Methyltestosterone/metabolism, Microsomes, Liver, Molecular Structure, Nandrolone/analogs & derivatives, Nandrolone/metabolism, Rats, Rats, Wistar
Pubmed
Web of science
Création de la notice
02/05/2017 14:32
Dernière modification de la notice
20/08/2019 13:37
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