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Glucuronidation of estrone and 16 alpha-hydroxyestrone by human UGT enzymes: The key roles of UGT1A10 and UGT2B7
Tekijät: Kallionpää RA, Järvinen E, Finel M
Kustantaja: PERGAMON-ELSEVIER SCIENCE LTD
Julkaisuvuosi: 2015
Journal: Journal of Steroid Biochemistry and Molecular Biology
Tietokannassa oleva lehden nimi: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Lehden akronyymi: J STEROID BIOCHEM
Vuosikerta: 154
Aloitussivu: 104
Lopetussivu: 111
Sivujen määrä: 8
ISSN: 0960-0760
DOI: https://doi.org/10.1016/j.jsbmb.2015.07.013
Tiivistelmä
The glucuronidation of estrone and 16 alpha-hydroxyestrone by recombinant human UDP-glucuronosyl-transferase enzymes (UGTs) of subfamilies 1A, 2A and 2B was studied. Microsomes from human liver and small intestine were also tested for the glucuronidation of these two estrogens. The results revealed that UGT1A10 is by far the most active enzyme in estrone glucuronidation. UGT1A10 also exhibited high rate of 16 alpha-hydroxyestrone conjugation at the 3-OH, whereas UGT2B7 catalyzed its glucuronidation at high rates at the 16-OH. Human liver microsomes exhibited high rates of 16 alpha-hydroxyestrone-16-glucuronide formation, but very low formation rates of either 16 alpha-hydroxyestrone-3-glucuronide or estrone glucuronide. On the other hand, human intestine microsomes catalyzed the formation of all these 3 different glucuronides at high rates. Kinetic analyses revealed very low K-m value for 16 alpha-hydroxyestrone glucuronidation by UGT2B7, below 4 mu M, suggesting higher affinity than commonly found among UGTs and their substrates. In further studies with UGT1A10, mutant F93G exhibited increased glucuronidation rates of 16 alpha-hydroxyestrone, but not estrone, whereas mutations in F90 did not reveal any activity with either estrogen. Taken together, the results of this study significantly expand our understanding on the metabolism of estrogens and their interactions with the human UGTs. (C) 2015 Elsevier Ltd. All rights reserved.
The glucuronidation of estrone and 16 alpha-hydroxyestrone by recombinant human UDP-glucuronosyl-transferase enzymes (UGTs) of subfamilies 1A, 2A and 2B was studied. Microsomes from human liver and small intestine were also tested for the glucuronidation of these two estrogens. The results revealed that UGT1A10 is by far the most active enzyme in estrone glucuronidation. UGT1A10 also exhibited high rate of 16 alpha-hydroxyestrone conjugation at the 3-OH, whereas UGT2B7 catalyzed its glucuronidation at high rates at the 16-OH. Human liver microsomes exhibited high rates of 16 alpha-hydroxyestrone-16-glucuronide formation, but very low formation rates of either 16 alpha-hydroxyestrone-3-glucuronide or estrone glucuronide. On the other hand, human intestine microsomes catalyzed the formation of all these 3 different glucuronides at high rates. Kinetic analyses revealed very low K-m value for 16 alpha-hydroxyestrone glucuronidation by UGT2B7, below 4 mu M, suggesting higher affinity than commonly found among UGTs and their substrates. In further studies with UGT1A10, mutant F93G exhibited increased glucuronidation rates of 16 alpha-hydroxyestrone, but not estrone, whereas mutations in F90 did not reveal any activity with either estrogen. Taken together, the results of this study significantly expand our understanding on the metabolism of estrogens and their interactions with the human UGTs. (C) 2015 Elsevier Ltd. All rights reserved.
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