TY - JOUR T1 - The Configuration of the 17-Hydroxy Group Variably Influences the Glucuronidation of β-Estradiol and Epiestradiol by Human UDP-Glucuronosyltransferases JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2307 LP - 2315 DO - 10.1124/dmd.108.022731 VL - 36 IS - 11 AU - Katriina Itäaho AU - Peter I. Mackenzie AU - Shin-ichi Ikushiro AU - John O. Miners AU - Moshe Finel Y1 - 2008/11/01 UR - http://dmd.aspetjournals.org/content/36/11/2307.abstract N2 - The glucuronidation of 17β-estradiol (β-estradiol) and 17α-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. The American Society for Pharmacology and Experimental Therapeutics ER -