Estradiol glucuronide

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]

Estradiol glucuronide
Names
IUPAC name
(2S,3S,4S,5R,6R)-3,4,5-Trihydroxy-6-[[(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-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
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
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

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]

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors
Estrogen Other names RBA (%)a REP (%)b
ER ERα ERβ
Estradiol E2 100 100 100
Estradiol 3-sulfate E2S; E2-3S ? 0.02 0.04
Estradiol 3-glucuronide E2-3G ? 0.02 0.09
Estradiol 17β-glucuronide E2-17G ? 0.002 0.0002
Estradiol benzoate EB; Estradiol 3-benzoate 10 1.1 0.52
Estradiol 17β-acetate E2-17A 31–45 24 ?
Estradiol diacetate EDA; Estradiol 3,17β-diacetate ? 0.79 ?
Estradiol propionate EP; Estradiol 17β-propionate 19–26 2.6 ?
Estradiol valerate EV; Estradiol 17β-valerate 2–11 0.04–21 ?
Estradiol cypionate EC; Estradiol 17β-cypionate ?c 4.0 ?
Estradiol palmitate Estradiol 17β-palmitate 0 ? ?
Estradiol stearate Estradiol 17β-stearate 0 ? ?
Estrone E1; 17-Ketoestradiol 11 5.3–38 14
Estrone sulfate E1S; Estrone 3-sulfate 2 0.004 0.002
Estrone glucuronide E1G; Estrone 3-glucuronide ? <0.001 0.0006
Ethinylestradiol EE; 17α-Ethynylestradiol 100 17–150 129
Mestranol EE 3-methyl ether 1 1.3–8.2 0.16
Quinestrol EE 3-cyclopentyl ether ? 0.37 ?
Footnotes: a = Relative binding affinities (RBAs) were determined via in-vitro displacement of labeled estradiol from estrogen receptors (ERs) generally of rodent uterine cytosol. Estrogen esters are variably hydrolyzed into estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented. b = Relative estrogenic potencies (REPs) were calculated from half-maximal effective concentrations (EC50) that were determined via in-vitro β‐galactosidase (β-gal) and green fluorescent protein (GFP) production assays in yeast expressing human ERα and human ERβ. Both mammalian cells and yeast have the capacity to hydrolyze estrogen esters. c = The affinities of estradiol cypionate for the ERs are similar to those of estradiol valerate and estradiol benzoate (figure). Sources: See template page.
Structural properties of selected estradiol esters
EstrogenStructureEster(s)Relative
mol. weight
Relative
E2 contentb
logPc
Position(s)Moiet(ies)TypeLengtha
Estradiol
1.001.004.0
Estradiol acetate
C3Ethanoic acidStraight-chain fatty acid21.150.874.2
Estradiol benzoate
C3Benzenecarboxylic acidAromatic fatty acid– (~4–5)1.380.724.7
Estradiol dipropionate
C3, C17βPropanoic acid (×2)Straight-chain fatty acid3 (×2)1.410.714.9
Estradiol valerate
C17βPentanoic acidStraight-chain fatty acid51.310.765.6–6.3
Estradiol benzoate butyrate
C3, C17βBenzoic acid, butyric acidMixed fatty acid– (~6, 2)1.640.616.3
Estradiol cypionate
C17βCyclopentylpropanoic acidAromatic fatty acid– (~6)1.460.696.9
Estradiol enanthate
C17βHeptanoic acidStraight-chain fatty acid71.410.716.7–7.3
Estradiol dienanthate
C3, C17βHeptanoic acid (×2)Straight-chain fatty acid7 (×2)1.820.558.1–10.4
Estradiol undecylate
C17βUndecanoic acidStraight-chain fatty acid111.620.629.2–9.8
Estradiol stearate
C17βOctadecanoic acidStraight-chain fatty acid181.980.5112.2–12.4
Estradiol distearate
C3, C17βOctadecanoic acid (×2)Straight-chain fatty acid18 (×2)2.960.3420.2
Estradiol sulfate
C3Sulfuric acidWater-soluble conjugate1.290.770.3–3.8
Estradiol glucuronide
C17βGlucuronic acidWater-soluble conjugate1.650.612.1–2.7
Estramustine phosphated
C3, C17βNormustine, phosphoric acidWater-soluble conjugate1.910.522.9–5.0
Polyestradiol phosphatee
C3–C17βPhosphoric acidWater-soluble conjugate1.23f0.81f2.9g
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 exposure). 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

References

  1. http://www.hmdb.ca/metabolites/HMDB10317
  2. 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.
  3. 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.
  4. 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.
  5. Düsterberg B, Nishino Y (1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–24. doi:10.1016/0378-5122(82)90064-0. PMID 7169965.
  6. Kelly Smith; Daniel M. Riche; Nickole Henyan (15 April 2010). Clinical Drug Data, 11th Edition. McGraw Hill Professional. ISBN 978-0-07-162686-6.
  7. Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA (October 2015). "The Regulation of Steroid Action by Sulfation and Desulfation". Endocr. Rev. 36 (5): 526–63. doi:10.1210/er.2015-1036. PMC 4591525. PMID 26213785.
  8. Järvinen E, Deng F, Kidron H, Finel M (April 2018). "Efflux transport of estrogen glucuronides by human MRP2, MRP3, MRP4 and BCRP". J. Steroid Biochem. Mol. Biol. 178: 99–107. doi:10.1016/j.jsbmb.2017.11.007. hdl:10138/321530. PMID 29175180.
  9. Zucchetti AE, Barosso IR, Boaglio AC, Basiglio CL, Miszczuk G, Larocca MC, Ruiz ML, Davio CA, Roma MG, Crocenzi FA, Pozzi EJ (March 2014). "G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis". Hepatology. 59 (3): 1016–29. doi:10.1002/hep.26752. hdl:2133/10484. PMID 24115158.
  10. Zhu BT, Conney AH (January 1998). "Functional role of estrogen metabolism in target cells: review and perspectives". Carcinogenesis. 19 (1): 1–27. doi:10.1093/carcin/19.1.1. PMID 9472688.
  11. Coldham NG, Dave M, Sivapathasundaram S, McDonnell DP, Connor C, Sauer MJ (July 1997). "Evaluation of a recombinant yeast cell estrogen screening assay". Environ. Health Perspect. 105 (7): 734–42. doi:10.1289/ehp.97105734. PMC 1470103. PMID 9294720.
  12. 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.


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