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Drug Metabolism and Disposition Fast Forward
First published on November 20, 2008; DOI: 10.1124/dmd.108.024844

0090-9556/09/3702-417-423$20.00
DMD 37:417-423, 2009

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UDP-Glucuronosyltransferases (UGTs) 2B7 and UGT2B17 Display Converse Specificity in Testosterone and Epitestosterone Glucuronidation, whereas UGT2A1 Conjugates Both Androgens Similarly

Taina Sten, Ingo Bichlmaier, Tiia Kuuranne, Antti Leinonen, Jari Yli-Kauhaluoma, and Moshe Finel

Centre for Drug Research (T.S., M.F.) and Division of Pharmaceutical Chemistry (T.S., I.B., J.Y.-K.), Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; and Doping Control Laboratory, United Laboratories Ltd., Helsinki, Finland (T.K., A.L.)

Testosterone and epitestosterone are endogenous steroids that differ in the configuration of the hydroxyl-bearing carbon at C-17. Testosterone is the predominant male sex hormone, whereas the role of epitestosterone is largely unclear. In humans, both androgens are excreted mainly as glucuronide conjugates and the urinary ratio of testosterone to epitestosterone (T/E), used to expose illicit testosterone abuse by male athletes, indicates the relative concentrations of the respective glucuronides. Some male athletes have T/E values greater than the accepted threshold value (4.0), even without testosterone abuse. We have analyzed athletes' urine samples and found that the main reason for such false-positive results in doping tests was a low epitestosterone glucuronide concentration not a high level of testosterone glucuronide. Sulfate conjugates of both testosterone and epitestosterone were also detected in the different urine samples. Glucuronidation assays with the 19 human UDP-glucuronosyltransferases (UGTs) of subfamilies UGT1A, UGT2A, and UGT2B revealed that UGT2B17 is the most active enzyme in testosterone glucuronidation. UGT2B17 does not glucuronidate epitestosterone, but inhibition studies revealed that it binds epitestosterone with affinity similar to that of testosterone. Epitestosterone glucuronidation is catalyzed mainly by UGT2B7, and the Km of this reaction is significantly lower than the Km of UGT2B17 for testosterone. Although UGT2B7 and UGT2B17 exhibited high, although converse, stereoselectivity in testosterone and epitestosterone glucuronidation, UGT2A1, an extrahepatic enzyme that is expressed mainly in the nasal epithelium, catalyzed the glucuronidation of both steroids at considerable rates and similar kinetics. The results shed new light on the substrate specificity and stereoselectivity of human UGTs.

Address correspondence to: Dr. Moshe Finel, Centre for Drug Research (CDR), Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5), FI-00014 University of Helsinki, Finland. E-mail: moshe.finel{at}helsinki.fi




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T. Sten, M. Kurkela, T. Kuuranne, A. Leinonen, and M. Finel
UDP-Glucuronosyltransferases in Conjugation of 5{alpha}- and 5{beta}-Androstane Steroids
Drug Metab. Dispos., November 1, 2009; 37(11): 2221 - 2227.
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