Chemistry:Estradiol glucuronide
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| Names | |
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| IUPAC name
3-Hydroxyestra-1,3,5(10)-trien-17β-yl β-D-glucopyranosiduronic acid
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| Systematic IUPAC name
(2S,3S,4S,5R,6R)-3,4,5-Trihydroxy-6-{[(1S,3aS,3bR,9bS,11aS)-7-hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthren-1-yl]oxy}oxane-2-carboxylic acid | |
| Other names
E217βG; 17β-Estradiol 17β-D-glucuronide; Estra-1,3,5(10)-triene-3,17β-diol 17β-D-glucuronoside
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| Identifiers | |
3D model (JSmol)
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| ChemSpider | |
| KEGG | |
PubChem CID
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| Properties | |
| C24H32O8 | |
| Molar mass | 448.512 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
| Infobox references | |
Estradiol glucuronide, or estradiol 17β-D-glucuronide, is a conjugated metabolite of estradiol.[1] It is formed from estradiol in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by the kidneys.[1] It has much higher water solubility than does estradiol.[1] Glucuronides are the most abundant estrogen conjugates.[1]
When exogenous estradiol is administered orally, it is subject to extensive first-pass metabolism (95%) in the intestines and liver.[2][3] A single administered dose of estradiol is absorbed 15% as estrone, 25% as estrone sulfate, 25% as estradiol glucuronide, and 25% as estrone glucuronide.[2] Formation of estrogen glucuronide conjugates is particularly important with oral estradiol as the percentage of estrogen glucuronide conjugates in circulation is much higher with oral ingestion than with parenteral estradiol.[2] Estradiol glucuronide can be converted back into estradiol, and a large circulating pool of estrogen glucuronide and sulfate conjugates serves as a long-lasting reservoir of estradiol that effectively extends its elimination half-life of oral estradiol.[2] In demonstration of the importance of first-pass metabolism and the estrogen conjugate reservoir in the pharmacokinetics of estradiol,[2] the elimination half-life of oral estradiol is 13 to 20 hours[4] whereas with intravenous injection its elimination half-life is only about 1 to 2 hours.[5]
Approximately 7% of estradiol is excreted in the urine as estradiol glucuronide.[6]
Estradiol glucuronide is transported into prostate gland, testis, and breast cells by OATP1A2, OATP1B1, OATP1B3, OATP1C1, and OATP3A1.[7] The ABC transporters MRP2, MRP3, MRP4, and BCRP, as well as several other transporters, have been found to transport estradiol glucuronide out of cells.[7][8]
The circulating concentrations of estrogen glucuronides are generally more than 10-fold lower than those of estrone sulfate, the most abundant estrogen conjugate in the circulation.[8]
Estradiol glucuronide has been identified as an agonist of the G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor.[9] This may be involved in estradiol glucuronide-induced cholestasis.[9]
Estrogen glucuronides can be deglucuronidated into the corresponding free estrogens by β-glucuronidase in tissues that express this enzyme, such as the mammary gland.[10] As a result, estrogen glucuronides have estrogenic activity via conversion into estrogens.[10]
Estradiol glucuronide shows about 300-fold lower potency in activating the estrogen receptors relative to estradiol in vitro.[11]
The positional isomer of estradiol glucuronide, estradiol 3-glucuronide, also occurs as a major endogenous metabolite of estradiol, circulating at two-thirds of the levels of estrone sulfate when it reaches its maximal concentrations just before ovulation and during the peak in estradiol levels that occurs at this time.[12]
Template:Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors
| Estrogen | Structure | Ester(s) | Relative mol. weight |
Relative E2 contentb |
logPc | ||||
|---|---|---|---|---|---|---|---|---|---|
| Position(s) | Moiet(ies) | Type | Lengtha | ||||||
| Estradiol |  |
– | – | – | – | 1.00 | 1.00 | 4.0 | |
| Estradiol acetate |  |
C3 | Ethanoic acid | Straight-chain fatty acid | 2 | 1.15 | 0.87 | 4.2 | |
| Estradiol benzoate |  |
C3 | Benzenecarboxylic acid | Aromatic fatty acid | – (~4–5) | 1.38 | 0.72 | 4.7 | |
| Estradiol dipropionate |  |
C3, C17β | Propanoic acid (×2) | Straight-chain fatty acid | 3 (×2) | 1.41 | 0.71 | 4.9 | |
| Estradiol valerate |  |
C17β | Pentanoic acid | Straight-chain fatty acid | 5 | 1.31 | 0.76 | 5.6–6.3 | |
| Estradiol benzoate butyrate |  |
C3, C17β | Benzoic acid, butyric acid | Mixed fatty acid | – (~6, 2) | 1.64 | 0.61 | 6.3 | |
| Estradiol cypionate |  |
C17β | Cyclopentylpropanoic acid | Aromatic fatty acid | – (~6) | 1.46 | 0.69 | 6.9 | |
| Estradiol enanthate |  |
C17β | Heptanoic acid | Straight-chain fatty acid | 7 | 1.41 | 0.71 | 6.7–7.3 | |
| Estradiol dienanthate |  |
C3, C17β | Heptanoic acid (×2) | Straight-chain fatty acid | 7 (×2) | 1.82 | 0.55 | 8.1–10.4 | |
| Estradiol undecylate |  |
C17β | Undecanoic acid | Straight-chain fatty acid | 11 | 1.62 | 0.62 | 9.2–9.8 | |
| Estradiol stearate |  |
C17β | Octadecanoic acid | Straight-chain fatty acid | 18 | 1.98 | 0.51 | 12.2–12.4 | |
| Estradiol distearate |  |
C3, C17β | Octadecanoic acid (×2) | Straight-chain fatty acid | 18 (×2) | 2.96 | 0.34 | 20.2 | |
| Estradiol sulfate |  |
C3 | Sulfuric acid | Water-soluble conjugate | – | 1.29 | 0.77 | 0.3–3.8 | |
| Estradiol glucuronide | |
C17β | Glucuronic acid | Water-soluble conjugate | – | 1.65 | 0.61 | 2.1–2.7 | |
| Estramustine phosphated |  |
C3, C17β | Normustine, phosphoric acid | Water-soluble conjugate | – | 1.91 | 0.52 | 2.9–5.0 | |
| Polyestradiol phosphatee |  |
C3–C17β | Phosphoric acid | Water-soluble conjugate | – | 1.23f | 0.81f | 2.9g | |
| Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic potency). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/[[hydrophobicity]]). Retrieved from PubChem, ChemSpider, and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = logP of repeat unit (i.e., estradiol phosphate). Sources: See individual articles. | |||||||||
See also
- Catechol estrogen
- Estradiol sulfate
- Estriol glucuronide
- Estriol sulfate
- Estrogen conjugate
- Lipoidal estradiol
- List of estrogen esters § Estradiol esters
References
- ↑ 1.0 1.1 1.2 1.3 "Human Metabolome Database: Showing metabocard for 17-beta-Estradiol glucuronide (HMDB0010317)". http://www.hmdb.ca/metabolites/HMDB10317.
- ↑ 2.0 2.1 2.2 2.3 2.4 Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 268–. ISBN 978-3-642-60107-1. https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA268.
- ↑ M. Notelovitz; P.A. van Keep (6 December 2012). The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28–November 2, 1984. Springer Science & Business Media. pp. 406–. ISBN 978-94-009-4145-8. https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA406.
- ↑ Stanczyk, Frank Z.; Archer, David F.; Bhavnani, Bhagu R. (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. ISSN 0010-7824. PMID 23375353.
- ↑ "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas 4 (4): 315–24. 1982. doi:10.1016/0378-5122(82)90064-0. PMID 7169965.
- ↑ Kelly Smith; Daniel M. Riche; Nickole Henyan (15 April 2010). Clinical Drug Data, 11th Edition. McGraw Hill Professional. ISBN 978-0-07-162686-6. https://books.google.com/books?id=bi6-qSVcRZwC.
- ↑ 7.0 7.1 "The Regulation of Steroid Action by Sulfation and Desulfation". Endocr. Rev. 36 (5): 526–63. October 2015. doi:10.1210/er.2015-1036. PMID 26213785.
- ↑ 8.0 8.1 "Efflux transport of estrogen glucuronides by human MRP2, MRP3, MRP4 and BCRP". J. Steroid Biochem. Mol. Biol. 178: 99–107. April 2018. doi:10.1016/j.jsbmb.2017.11.007. PMID 29175180.
- ↑ 9.0 9.1 "G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17β-D-glucuronide-induced cholestasis". Hepatology 59 (3): 1016–29. March 2014. doi:10.1002/hep.26752. PMID 24115158.
- ↑ 10.0 10.1 "Functional role of estrogen metabolism in target cells: review and perspectives". Carcinogenesis 19 (1): 1–27. January 1998. doi:10.1093/carcin/19.1.1. PMID 9472688.
- ↑ "Evaluation of a recombinant yeast cell estrogen screening assay". Environ. Health Perspect. 105 (7): 734–42. July 1997. doi:10.1289/ehp.97105734. PMID 9294720.
- ↑ F. A. Kincl; J. R. Pasqualini (22 October 2013). Hormones and the Fetus: Volume 1: Production, Concentration and Metabolism During Pregnancy. Elsevier Science. pp. 39–. ISBN 978-1-4832-8538-2. https://books.google.com/books?id=0ly2AgAAQBAJ&pg=PA39.
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