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The Configuration of the 17-Hydroxy Group Variably Influences the Glucuronidation of β-Estradiol and Epiestradiol by Human UDP-Glucuronosyltransferases

Division of Pharmaceutical Chemistry (K.I.) and Center for Drug Research (M.F.), Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, South Australia, Australia (P.I.M., J.O.M.); and Department of Biotechnology, Toyama Prefectural University, Toyama, Japan (S.-i.I.)

The glucuronidation of 17β-estradiol (β-estradiol) and 17-estradiol (epiestradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. Recombinant human UDP-glucuronosyltransferases (UGTs) UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A10 conjugated one or both diastereomers, mainly at the 3-OH. The activity of UGT1A4 was low and unique because it was directed merely toward the 17-OH of both aglycones. UGT1A10 exhibited particularly high estradiol glucuronidation activity, the rate and affinity of which were significantly higher in the case of β-estradiol than with epiestradiol. UGT1A9 did not catalyze estradiol glucuronidation, but UGT1A9-catalyzed scopoletin glucuronidation was competitively inhibited by β-estradiol. UGT2B4, UGT2B7, and UGT2B17 exclusively conjugated the estradiols at the 17-OH position in a highly stereoselective fashion. UGT2B4 was specific for epiestradiol; UGT2B7 glucuronidated both diastereomers, with high affinity for epiestradiol, whereas UGT2B17 only glucuronidated β-estradiol. UGT2B15 glucuronidated both estradiols at the 3-OH, with a strong preference for epiestradiol. Human UGT2A1 and UGT2A2 glucuronidated both diastereoisomers at both hydroxyl groups. Microsomal studies revealed that human liver mainly yielded epiestradiol 17-O-glucuronide, and human intestine primarily yielded β-estradiol 3-O-glucuronide, whereas rat liver preferentially formed β-estradiol 17-O-glucuronide. Of the three recombinant rat UGTs that were examined in this study, rUGT2B1 was specific for the 17-OH of β-estradiol, rUGT2B2 did not catalyze estradiol glucuronidation, whereas rUGT2B3 exhibited high activity toward the 17-OH in both diastereoisomers. The results show that although many UGTs can catalyze estradiol glucuronidation, there are marked differences in their kinetics, regioselectivity, and stereoselectivity.

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