Tmic
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Record Information
Version2.0
Creation Date2014-09-11 05:16:42 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4790
Identification
Common NameEstriol
ClassSmall Molecule
DescriptionA hydroxylated metabolite of estradiol or estrone that has a hydroxyl group at C3-beta, 16-alpha, and 17-beta position. Estriol is a major urinary estrogen. During pregnancy, large amount of estriol is produced by the placenta. Isomers with inversion of the hydroxyl group or groups are called epiestriol. Though estriol is used as part of the primarily North American phenomenon of bioidentical hormone replacement therapy, it is not approved for use by the FDA or Health Canada. It is however available in the United States by prescription filled only by compounding pharmacies. It has also been approved and marketed throughout Europe and Asia for approximately 40 years for the treatment of post-menopausal hot flashes.
Compound Type
  • Animal Toxin
  • Drug
  • Food Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(16alpha,17beta)-Estra-1,3,5(10)-triene-3,16,17-triol
(16α,17β)-estra-1,3,5(10)-triene-3,16,17-triol
1,3,5(10)-Estratriene-3,16-alpha,17beta-triol
13b-Methyl-1,3,5(10)-gonatriene-3,16a,17b-triol
16-alpha,17-beta-Estriol
16-alpha,17-beta-Oestriol
16-alpha-Hydroxyestradiol
16a,17b-Estriol
16a-Estriol
16a-Hydroxyestradiol
16alpha,17beta-Estriol
16alpha,17beta-Oestriol
16alpha-Hydroxy-17beta-estradiol
16alpha-Hydroxyestradiol
16alpha-Hydroxyoestradiol
16α-hydroxyestradiol
3,16a,17b-Estriol
3,16a,17b-Trihydroxyestra-1,3,5(10)-triene
3,16alpha,17beta-Trihydroxy-1,3,5(10)-estratriene
3,16alpha,17beta-Trihydroxy-delta(1,3,5)-estratriene
3,16alpha,17beta-Trihydroxyestra-1,3,5(10)-triene
Aacifemine
Colpoestriol
Colpogyn
Colpovister
Destriol
Deuslon A
Deuslon-A
Estra-1,3,5(10)-triene-3,16a,17b-triol
Estratriol
Estriel
Follicular hormone hydrate
Gynasan
Hemostyptanon
Holin V
Hormomed
Incurin
Klimax E
Klimoral
Oekolp
Oestratriol
Oestriol
Oestriolum
Orestin
Orgastyptin
Ortho-Gynest
Ovesterin
Ovestin
Ovestinon
Ovestrion
Ovo-Vinces
Synapause E
Theelol
Tridestrin
Trihydroxyestrin
Triovex
Chemical FormulaC18H24O3
Average Molecular Mass288.381 g/mol
Monoisotopic Mass288.173 g/mol
CAS Registry Number50-27-1
IUPAC Name(1S,10R,11S,13R,14R,15S)-15-methyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-2(7),3,5-triene-5,13,14-triol
Traditional Name(1S,10R,11S,13R,14R,15S)-15-methyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-2(7),3,5-triene-5,13,14-triol
SMILES[H][C@@]1(O)C[C@@]2([H])[C@]3([H])CCC4=CC(O)=CC=C4[C@@]3([H])CC[C@]2(C)[C@@]1([H])O
InChI IdentifierInChI=1S/C18H24O3/c1-18-7-6-13-12-5-3-11(19)8-10(12)2-4-14(13)15(18)9-16(20)17(18)21/h3,5,8,13-17,19-21H,2,4,6-7,9H2,1H3/t13-,14-,15+,16-,17+,18+/m1/s1
InChI KeyInChIKey=PROQIPRRNZUXQM-ZXXIGWHRSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassEstrane steroids
Direct ParentEstrogens and derivatives
Alternative Parents
Substituents
  • Estrogen-skeleton
  • 3-hydroxysteroid
  • 17-hydroxysteroid
  • 16-hydroxysteroid
  • 16-alpha-hydroxysteroid
  • Hydroxysteroid
  • Phenanthrene
  • Tetralin
  • 1-hydroxy-2-unsubstituted benzenoid
  • Benzenoid
  • Cyclic alcohol
  • Secondary alcohol
  • 1,2-diol
  • Polyol
  • Organooxygen compound
  • Hydrocarbon derivative
  • Alcohol
  • Organic oxygen compound
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Endoplasmic reticulum
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Adrenal Cortex
  • Adrenal Gland
  • Kidney
  • Liver
  • Placenta
  • Testes
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point82-86°C
Boiling PointNot Available
SolubilityNot Available
LogP2.45
Predicted Properties
PropertyValueSource
Water Solubility0.12 g/LALOGPS
logP2.54ALOGPS
logP2.67ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)10.33ChemAxon
pKa (Strongest Basic)-3.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area60.69 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity81.27 m³·mol⁻¹ChemAxon
Polarizability33.08 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-MS (3 TMS)splash10-005a-1983000000-2f46d0d29b48132f7670View in MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-000i-4970000000-1aa2bbf3f32fd687c37dView in MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-005a-1983000000-2f46d0d29b48132f7670View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0ab9-1390000000-492aa66975c4e026b9d8View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-009i-2033900000-46c301a46b654b6c6bf3View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0a4i-5900000000-2102cb581ac98fea87b0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-0a4i-1900000000-1fab12be883127f80c67View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-0a4i-5900000000-2102cb581ac98fea87b0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (JEOL JMS-01-SG-2) , Positivesplash10-000i-4970000000-1aa2bbf3f32fd687c37dView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Linear Ion Trap , negativesplash10-000i-0390000000-891430228022fb330b42View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0190000000-b047d204e97271aa8a65View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00dr-0490000000-c0c0bd8b1dc1381c06faView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0ufr-3950000000-b7180dbe548021fd7fc9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000i-0090000000-743915792d6f69593b2bView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-000i-0090000000-8469d578b4631e8de995View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-02p0-0190000000-738399876b56d0e183d5View in MoNA
MSMass Spectrum (Electron Ionization)splash10-000i-3950000000-c2f0781bc5056d66aaf5View in MoNA
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableView in JSpectraViewer
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityEstriol levels can be measured to give an indication of the general health of the fetus. DHEA-S is produced by the adrenal cortex of the fetus. This is converted to estriol by the placenta. If levels of "unconjugated estriol" are abnormally low in a pregnant woman, this may indicate a problem with the development of the child. The drug interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estriol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
MetabolismNot Available
Toxicity ValuesORAL (LD50): Acute: >2000 mg/kg [Rat].
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed as a test to determine the general health of an unborn fetus.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB04573
HMDB IDHMDB00153
PubChem Compound ID5756
ChEMBL IDCHEMBL193482
ChemSpider ID5553
KEGG IDC05141
UniProt IDNot Available
OMIM ID
ChEBI ID27974
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDESL
ACToR IDNot Available
Wikipedia LinkEstriol
References
Synthesis Reference

James V. Freeman, Gary M. Johnson, “Synthesis of 6.alpha.-functionalized estriol haptens and protein conjugates thereof.” U.S. Patent US5902888, issued June, 1973.

MSDSLink
General References
  1. Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR: Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol. 2003 Dec 1;171(11):6267-74. [14634144 ]
  2. Diczfalusy E: The early history of estriol. J Steroid Biochem. 1984 Apr;20(4B):945-53. [6374294 ]
  3. Kashork CD, Sutton VR, Fonda Allen JS, Schmidt DE, Likhite ML, Potocki L, O'Brien WE, Shaffer LG: Low or absent unconjugated estriol in pregnancy: an indicator for steroid sulfatase deficiency detectable by fluorescence in situ hybridization and biochemical analysis. Prenat Diagn. 2002 Nov;22(11):1028-32. [12424769 ]
  4. Furuhashi N, Tsujiei M: [Clinical significance of serum and urinary estriol analysis in endocrine tests of the gonadal and placental system]. Nihon Rinsho. 1989 Dec;48 Suppl:1260-2. [2621854 ]
  5. Ronin-Walknowska E, Szczygielski A, Skoczowska M: [Usefulness of determining free estriol, placental lactogen, progesterone, placental alkaline phosphatase, uric acid, hematocrit, hemoglobin and proteins in the blood and estrogen in the urine in the prognosis of the status of newborn infants in EPH gestosis]. Ginekol Pol. 1987 Jan;58(1):21-6. [3583036 ]
  6. Fredricsson B, Carlstrom K, Eneroth P: Short-term variations in urinary estriol and renal function. Possible effects of extraneous conditions. Gynecol Obstet Invest. 1978;9(5):268-76. [752645 ]
  7. Andreolini F, Borra C, Caccamo F, Di Corcia A, Nicoletti I, Samperi R, Improta F: Estriol and its conjugates in late pregnancy determined by extraction with Carbopack B and liquid chromatography with fluorometric detection. Clin Chem. 1985 Oct;31(10):1698-702. [2994907 ]
  8. Truran PL, Read GF, Walker S: Radioimmunoassay for salivary estriol, with use of an 125I radioligand and a solid-phase separation technique. Clin Chem. 1982 Dec;28(12):2393-7. [7139918 ]
  9. Izumi H, Saito N, Ichiki S, Makino Y, Yukitake K, Kaneoka T: Prenatal diagnosis of congenital lipoid adrenal hyperplasia. Obstet Gynecol. 1993 May;81(5 ( Pt 2)):839-41. [8469492 ]
  10. Guedeney X, Chanez C, Grenier A, Scherrmann JM: Temperature-dependent immunoreactive assay to screen for digoxin-like immunoreactive factor(s). Clin Chem. 1991 Nov;37(11):1900-4. [1718632 ]
  11. Andreolini F, Di Corcia A, Lagana A, Samperi R, Raponi G: Preliminary isolation of urinary placental estriol before gas or liquid chromatography. Clin Chem. 1983 Dec;29(12):2076-8. [6640903 ]
  12. Evans JJ, Wilkinson AR, Aickin DR: Salivary estriol concentrations during normal pregnancies, and a comparison with plasma estriol. Clin Chem. 1984 Jan;30(1):120-1. [6690116 ]
  13. Kono H, Furuhashi N, Shinkawa O, Takahashi T, Tsujiei M, Yajima A: The maternal serum cortisol levels after onset of labor. Tohoku J Exp Med. 1987 Jun;152(2):133-7. [3629582 ]
  14. Moore ML: Biochemical markers for preterm labor and birth: what is their role in the care of pregnant women? MCN Am J Matern Child Nurs. 1999 Mar-Apr;24(2):80-6. [10083784 ]
  15. Pentikainen PJ, Pentikainen LA, Azarnoff DL, Dujovne CA: Plasma levels and excretion of estrogens in urine in chronic lever disease. Gastroenterology. 1975 Jul;69(1):20-7. [1171044 ]
  16. Nutman A, Freud E, Itzhaky D, Dolfin T, Tepper R: High maternal estriol level in pregnancy as a predictor of surgical intervention for undescended testis. Fertil Steril. 2005 Jul;84(1):249-52. [16009196 ]
  17. Pasqualini JR: Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments. J Steroid Biochem Mol Biol. 2005 Dec;97(5):401-15. Epub 2005 Oct 3. [16202579 ]
  18. Lardy H, Marwah A, Marwah P: C(19)-5-ene steroids in nature. Vitam Horm. 2005;71:263-99. [16112271 ]
  19. Shinawi M, Szabo S, Popek E, Wassif CA, Porter FD, Potocki L: Recognition of Smith-Lemli-Opitz syndrome (RSH) in the fetus: utility of ultrasonography and biochemical analysis in pregnancies with low maternal serum estriol. Am J Med Genet A. 2005 Sep 15;138(1):56-60. [16097001 ]
  20. Trimesta [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.00203 uMACEA_T47D_80hr_PositiveACEA Biosciences
AC500.0489 uMATG_ERa_TRANSAttagene
AC500.0229 uMNVS_NR_hERNovascreen
AC500.666 uMOT_ER_ERaERa_0480Odyssey Thera
AC500.438 uMOT_ER_ERaERa_1440Odyssey Thera
AC500.224 uMOT_ERa_EREGFP_0120Odyssey Thera
AC500.212 uMOT_ERa_EREGFP_0480Odyssey Thera
AC500.000821 uMTox21_ERa_BLA_Agonist_ratioTox21/NCGC
AC500.000589 uMTox21_ERa_LUC_BG1_AgonistTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular Weight:
59215.765 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.1 uMOT_ER_ERaERb_0480Odyssey Thera
AC500.189 uMOT_ER_ERaERb_1440Odyssey Thera
AC500.157 uMOT_ER_ERbERb_0480Odyssey Thera
AC500.1 uMOT_ER_ERbERb_1440Odyssey Thera
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:
AR
Uniprot ID:
P10275
Molecular Weight:
98987.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC502.15 uMNVS_NR_hARNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation.Isoform A: inactive in stimulating c-Src/MAPK signaling on hormone stimulation.Isoform 4: Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone.
Gene Name:
PGR
Uniprot ID:
P06401
Molecular Weight:
98979.96 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC502.3 uMNVS_NR_hPRNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]