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GLUCURONIDATION OF ANABOLIC ANDROGENIC STEROIDS BY RECOMBINANT HUMAN UDP-GLUCURONOSYLTRANSFERASES

Division of Pharmaceutical Chemistry (T.K.) and Viikki Drug Discovery Technology Center (DDTC) (T.K., M.K., M.F., R.K.), Department of Pharmacy, University of Helsinki, Finland; and Institute of Biochemistry (M.T., W.S.), German Sport University, Cologne, Germany

A multidimensional study on the glucuronidation of anabolic androgenic steroids and their phase I metabolites by 11 recombinant human UDP-glucuronosyltransferases (UGTs) was carried out using liquid chromatographic-tandem mass spectrometric analyses. Large differences between the enzymes with respect to the conjugation profiles of the 11 tested aglycones were detected. Two UGTs, 1A6 and 1A7, did not exhibit measurable activity toward any of the aglycones that were examined in this study. Regioselectivity was demonstrated by UGTs 1A8, 1A9, and 2B15 that preferentially catalyzed hydroxyl glucuronidation at the 17ß-position. Most of the other enzymes glucuronidated hydroxyl groups at both the 3- and the 17ß-positions. Clear stereoselectivity was observed in glucuronidation of diastereomeric nandrolone metabolites (5-estran-3-ol-17-one and 5ß-estran-3-ol-17-one), whereas such specificity was not seen when analogous methyltestosterone metabolites were assayed. UGTs 1A1, 1A3, 1A4, 1A8, 1A9, 1A10, 2B4, 2B7, and 2B15 readily glucuronidated 5-androstane-3,17ß-diol, but none of them exhibited methyltestosterone glucuronidation activity. In agreement with the latter observations, we found that the methyltestosterone glucuronidation activity of human liver microsomes is extremely low, whereas in induced rat liver microsomes it was significantly higher. The homology among UGTs 1A7 to 1A10 at the level of amino acid sequence is very high, and it was thus surprising to find large differences in their activity toward this set of aglycones. Furthermore, the high activity of UGT1A8 and 1A10 toward some of the substrates indicates that extrahepatic enzymes might play a role in the metabolism of anabolic androgenic steroids.

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