title: The configuration of the 17-hydroxy group variably influences the glucuronidation of beta-estradiol and epiestradiol by human UDP-glucuronosyltransferases.
abstract: The glucuronidation of 17beta-estradiol (beta-estradiol) and 17alpha-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 beta-estradiol than with epiestradiol. UGT1A9 did not catalyze estradiol glucuronidation, but UGT1A9-catalyzed scopoletin glucuronidation was competitively inhibited by beta-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 beta-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 beta-estradiol 3-O-glucuronide, whereas rat liver preferentially formed beta-estradiol 17-O-glucuronide. Of the three recombinant rat UGTs that were examined in this study, rUGT2B1 was specific for the 17-OH of beta-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.
authors: Division of Pharmaceutical Chemistry, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5), University of Helsinki, FIN-00014 Helsinki, Finland.
authors: Katriina
authors: K
authors: Itäaho
authors: Peter I
authors: PI
authors: Mackenzie
authors: Shin-ichi
authors: S
authors: Ikushiro
authors: John O
authors: JO
authors: Miners
authors: Moshe
authors: M
authors: Finel
mesh_terms: D000818:Animals; D002384:Catalysis; D002417:Cattle; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry* / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism; D013552:Swine
chemical_list: D020719:Glucuronides; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D014453:Glucuronosyltransferase