Regiospecificity and stereospecificity of human UDP-glucuronosyltransferases in the glucuronidation of estriol, 16-epiestriol, 17-epiestriol, and 13-epiestradiol
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 V(max) 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.
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Estriol and 16α-hydroxyestrone are conjugated at the 3-hydroxygroup by UGT1A10 and at the 16α-hydroxy group by UGT2B7.
“Estriol and 16α-hydroxyestrone are conjugated at the 3-hydroxygroup by UGT1A10 and at the 16α-hydroxy group by UGT2B7 [330,331].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [331]
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- Authors
- Sneitz, N., Vahermo, M., Mosorin, J., Laakkonen, L., Poirier, D., & Finel, M.
- Affiliations
- University of Helsinki (FI)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 41
- Issue
- 3
- Pages
- 582-591
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2099103888
- Cited by
- 31
- References
- 26
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 1 · 2019: 3 · 2018: 3 · 2017: 4 · 2015: 2 · 2014: 4 · 2013: 1
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- UDP-glucuronosyltransferase, glucuronidation, estriol, UGT1A10, UGT2B7, UGT2B17, regiospecificity, stereospecificity, estrogen metabolism, liver microsomes, intestinal microsomes
- MeSH terms
- Biotransformation, Estradiol, Estriol, Humans, Hydroxylation, Isoenzymes, Kinetics, Models, Molecular, Mutation, Recombinant Proteins, Stereoisomerism, Structure-Activity Relationship, Substrate Specificity, Glucuronosyltransferase, Molecular Structure, Minor Histocompatibility Antigens
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