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Estradiol glucuronide

Not to be confused with Estradiol 3-glucuronide.
Estradiol glucuronide
Names
IUPAC name
3-Hydroxyestra-1,3,5(10)-trien-17β-yl β-D-glucopyranosiduronic acid
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
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
  • InChI=1S/C24H32O8/c1-24-9-8-14-13-5-3-12(25)10-11(13)2-4-15(14)16(24)6-7-17(24)31-23-20(28)18(26)19(27)21(32-23)22(29)30/h3,5,10,14-21,23,25-28H,2,4,6-9H2,1H3,(H,29,30)/t14-,15-,16+,17+,18+,19+,20-,21+,23-,24+/m1/s1
    Key: MTKNDAQYHASLID-QXYWQCSFSA-N
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)C(=O)O)O)O)O)CCC5=C3C=CC(=C5)O
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).

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]

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors
Estrogen Other names RBATooltip Relative binding affinity (%)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
Estrogen Structure Ester(s) Relative
mol. weight		 Relative
E2 contentb		 log Pc
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 Benzoic 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 Cyclic 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 or cyclic 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 = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

See also

References

  1. ^ a b c d "Human Metabolome Database: Showing metabocard for 17-beta-Estradiol glucuronide (HMDB0010317)".
  2. ^ a b c d e 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. ^ a b 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. ^ a b 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. S2CID 3678002.
  9. ^ a b 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 17β-D-glucuronide-induced cholestasis". Hepatology. 59 (3): 1016–29. doi:10.1002/hep.26752. hdl:2133/10484. PMID 24115158. S2CID 20568614.
  10. ^ a b 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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