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Research ArticleArticle

Regiospecificity and Stereospecificity of Human UDP-Glucuronosyltransferases in the Glucuronidation of Estriol, 16-Epiestriol, 17-Epiestriol, and 13-Epiestradiol

Nina Sneitz, Mikko Vahermo, Johanna Mosorin, Liisa Laakkonen, Donald Poirier and Moshe Finel
Drug Metabolism and Disposition March 2013, 41 (3) 582-591; DOI: https://doi.org/10.1124/dmd.112.049072
Nina Sneitz
Centre for Drug Research (N.S., J.M., L.L., M.F.) and Division of Pharmaceutical Chemistry (N.S., M.V.), Faculty of Pharmacy, University of Helsinki, Finland; and CHUQ-CHUL Research Center and Laval University, Quebec City, Québec, Canada (D.P.)
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Mikko Vahermo
Centre for Drug Research (N.S., J.M., L.L., M.F.) and Division of Pharmaceutical Chemistry (N.S., M.V.), Faculty of Pharmacy, University of Helsinki, Finland; and CHUQ-CHUL Research Center and Laval University, Quebec City, Québec, Canada (D.P.)
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Johanna Mosorin
Centre for Drug Research (N.S., J.M., L.L., M.F.) and Division of Pharmaceutical Chemistry (N.S., M.V.), Faculty of Pharmacy, University of Helsinki, Finland; and CHUQ-CHUL Research Center and Laval University, Quebec City, Québec, Canada (D.P.)
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Liisa Laakkonen
Centre for Drug Research (N.S., J.M., L.L., M.F.) and Division of Pharmaceutical Chemistry (N.S., M.V.), Faculty of Pharmacy, University of Helsinki, Finland; and CHUQ-CHUL Research Center and Laval University, Quebec City, Québec, Canada (D.P.)
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Donald Poirier
Centre for Drug Research (N.S., J.M., L.L., M.F.) and Division of Pharmaceutical Chemistry (N.S., M.V.), Faculty of Pharmacy, University of Helsinki, Finland; and CHUQ-CHUL Research Center and Laval University, Quebec City, Québec, Canada (D.P.)
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Moshe Finel
Centre for Drug Research (N.S., J.M., L.L., M.F.) and Division of Pharmaceutical Chemistry (N.S., M.V.), Faculty of Pharmacy, University of Helsinki, Finland; and CHUQ-CHUL Research Center and Laval University, Quebec City, Québec, Canada (D.P.)
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Abstract

The glucuronidation of estriol, 16-epiestriol, and 17-epiestriol by the human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A, and 2B was examined. UGT1A10 is highly active in the conjugation of the 3-OH in all these estriols, whereas UGT2B7 is the most active UGT toward one of the ring D hydroxyls, the 16-OH in estriol and 16-epiestriol, but the 17-OH in 17-epiestriol. Kinetic analyses indicated that the 17-OH configuration plays a major role in the affinity of UGT2B7 for estrogens. The glucuronidation of the different estriols by the human liver and intestine microsomes reflects the activity of UGT1A10 and UGT2B7 in combination with the tissues’ difference in UGT1A10 expression. The UGT1A10 mutant 1A10-F93G exhibited much higher Vmax values than UGT1A10 in estriol and 17-epiestriol glucuronidation, but a significantly lower value in 16-epiestriol glucuronidation. To this study on estriol glucuronidation we have added experiments with 13-epiestradiol, a synthetic estradiol in which the spatial arrangement of the methyl on C18 and the hydroxyl on C17 is significantly different than in other estrogens. In comparison with estradiol glucuronidation, the C13 configuration change decreases the turnover of UGTs that conjugate the 3-OH, but increases it in UGTs that primarily conjugate the 17-OH. Unexpectedly, UGT2B17 exhibited similar conjugation rates of both the 17-OH and 3-OH of 13-espiestradiol. The combined results reveal the strong preference of UGT1A10 for the 3-OH of physiologic estrogens and the equivalently strong preference of UGT2B7 and UGT2B17 for the hydroxyls on ring D of such steroid hormones.

Footnotes

  • Financial support was obtained from the Sigrid Juselius Foundation; the Magnus Ehrnrooth Foundation; and the Academy of Finland [Grant 260010].

  • dx.doi.org/10.1124/dmd.112.049072.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received September 15, 2012.
  • Accepted January 3, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (3)
Drug Metabolism and Disposition
Vol. 41, Issue 3
1 Mar 2013
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Research ArticleArticle

Glucuronidation of Estrogen Stereoisomers

Nina Sneitz, Mikko Vahermo, Johanna Mosorin, Liisa Laakkonen, Donald Poirier and Moshe Finel
Drug Metabolism and Disposition March 1, 2013, 41 (3) 582-591; DOI: https://doi.org/10.1124/dmd.112.049072

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Research ArticleArticle

Glucuronidation of Estrogen Stereoisomers

Nina Sneitz, Mikko Vahermo, Johanna Mosorin, Liisa Laakkonen, Donald Poirier and Moshe Finel
Drug Metabolism and Disposition March 1, 2013, 41 (3) 582-591; DOI: https://doi.org/10.1124/dmd.112.049072
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