کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1991305 | 1540995 | 2015 | 8 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Glucuronidation of estrone and 16α-hydroxyestrone by human UGT enzymes: The key roles of UGT1A10 and UGT2B7 Glucuronidation of estrone and 16α-hydroxyestrone by human UGT enzymes: The key roles of UGT1A10 and UGT2B7](/preview/png/1991305.png)
• Glucuronidation of estrone and 16α-hydroxyestrone by 19 human UGTs was examined.
• Extrahepatic UGT1A10 rapidly conjugates the 3-OH of both E1 and 16α-OHE1.
• The 16-OH of 16α-OHE1 is conjugated by UGT2B7 at high affinity.
• Assays with human liver and intestine microsomes support recombinant UGTs results.
• The UGT1A10-F93G mutant favors glucuronidation of estrogens with ring D substituents.
The glucuronidation of estrone and 16α-hydroxyestrone by recombinant human UDP-glucuronosyltransferase 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 16α-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 16α-hydroxyestrone-16-glucuronide formation, but very low formation rates of either 16α-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 Km value for 16α-hydroxyestrone glucuronidation by UGT2B7, below 4 μM, suggesting higher affinity than commonly found among UGTs and their substrates. In further studies with UGT1A10, mutant F93G exhibited increased glucuronidation rates of 16α-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.
Journal: The Journal of Steroid Biochemistry and Molecular Biology - Volume 154, November 2015, Pages 104–111