Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium
Abstract
Uridine diphospho-glucuronosyltransferases (UGTs) inactivate and facilitate the excretion of estrogens to glucuronides (-G), the most abundant circulating estrogen conjugates. The identity of the conjugated estrogens formed by all known overexpressed UGTs (n = 16) was analyzed by comparison with retention time and mass fragmentation of authentic standards by HPLC tandem mass spectrometry methods. Six UGTs, namely 1A1, 1A3, 1A8, 1A9, 1A10, and 2B7, were found to glucuronidate estradiol (E(2)) and estrone (E(1)), their hydroxyls (OH), and their methoxy derivatives (MeO). Addition of glucuronic acid was catalyzed by specific UGTs at positions 2, 3, and 4 of the estrogens, whereas only E(2) was conjugated at position 17 by UGT2B7. Kinetic parameters indicate that the conjugation of E(2) at position 3 was predominantly catalyzed by 1A1, 1A3, and 1A8 and by 1A8 for E(1). Conjugation of 2-OHE(1)/E(2) and 2- and 4-MeOE(1)/E(2) was selective at position 3, mostly catalyzed by 1A1 and 1A8. Of all UGTs, UGT2B7 demonstrated the highest catalytic activities for estrogens and at least 10- to 50-fold higher activity for the conjugation of genotoxic 4-hydroxycatecholestrogens at position 4, compared with the conjugation of E(2), E(1), and 2-hydroxycatecholestrogens. Its presence was further shown in the endometrium by RT-PCR and immunohistochemistry, localizing in the same cells expressing CYP1B1, involved locally in the formation of 4-hydroxycatecholestrogens. Data show that several UGT enzymes detected in the endometrium are involved in the glucuronidation of E(2) and its 2-OH, 4-OH, and 2-MeO metabolites that exert various biological effects in the tissue.
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Catecholestrogens can additionally be glucuronidated in positions 2 and 4.
“Catcholestrogens can additionally be glucuronidated in positions 2 and 4 [332].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [332]
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- Authors
- Lépine, J., Bernard, O., Plante, M., Têtu, B., Pelletier, G., Labrie, F., Bélanger, A., & Guillemette, C.
- Affiliations
- Department of Molecular Endocrinology and Oncology (J.L., O.B., G.P., F.L., A.B., C.G.), G1V 4G2 Québec, Canada
- Université Laval (CA)
- Hôtel-Dieu de Québec (CA)
- Department of Pathology Hôtel-Dieu de Québec (B.T.), G1K 7P4 Québec, Canada
- Centre hospitalier de l'Université Laval (CA)
- Corresponding author
- Guillemette, Chantal
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-10-01
- Volume
- 89
- Issue
- 10
- Pages
- 5222-5232
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2013903932
- Cited by
- 205
- References
- 51
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 10 · 2017: 5 · 2016: 8 · 2015: 9 · 2014: 10 · 2013: 13 · 2012: 7
- FWCI
- 9.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Université Laval
- Canadian Institutes of Health Research
- 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
- estradiol, estrone, catechol estrogens, regioselectivity, UGT2B7, UGT1A1, UGT1A8, UGT1A3, UGT1A10, UGT1A9, endometrium, CYP1B1, glucuronide conjugates
- MeSH terms
- UGT1A1 Enzyme, Estrogens, Catechol, Cell Line, Endometrium, Estradiol, Estrone, Female, Humans, Kidney, Substrate Specificity, Glucuronosyltransferase, Gene Expression Regulation, Enzymologic, Glucuronic Acid
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