 | |
| Names | |
|---|---|
| IUPAC name Estra-1,3,5(10)-triene-2,3,17β-triol | |
| Systematic IUPAC name (1S,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,7,8-triol | |
| Other names 2-OHE2 | |
| Identifiers | |
| |
3D model (JSmol) | |
| ChemSpider | |
| ECHA InfoCard | 100.160.393 |
| UNII | |
| |
| |
| Properties | |
| C18H24O3 | |
| Molar mass | 288.387 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
2-Hydroxyestradiol (2-OHE2), also known asestra-1,3,5(10)-triene-2,3,17β-triol, is anendogenoussteroid,catechol estrogen, andmetabolite ofestradiol, as well as apositional isomer ofestriol.[1]
Transformation of estradiol to 2-hydroxyestradiol is a majormetabolic pathway of estradiol in theliver.[1]CYP1A2 andCYP3A4 are the majorenzymes catalyzing the 2-hydroxylation of estradiol.[1] Conversion of estradiol into 2-hydroxyestradiol has also been detected in theuterus,breast,kidney,brain, andpituitary gland, as well as theplacenta, and may similarly be mediated bycytochrome P450 enzymes.[1] Although estradiol is extensively converted into 2-hydroxyestradiol, circulating levels of 2-hydroxyestradiol and levels of 2-hydroxyestradiol in various tissues are very low.[1] This may be due to rapidconjugation (O-methylation,glucuronidation,sulfonation) of 2-hydroxyestradiol followed byurinaryexcretion.[1]
2-Hydroxyestradiol has approximately 7% and 11% of theaffinity of estradiol at theestrogen receptors (ERs)ERα andERβ, respectively.[2] It dissociates from the estrogen receptors more rapidly than does estradiol.[3] The steroid is only very weaklyestrogenic, and is able toantagonize the estrogenic effects of estradiol, indicating that itsintrinsic activity at theestrogen receptor is less than that of estradiol and hence that it possesses the profile of aselective estrogen receptor modulator.[1] It shows estrogenic activity in humanbreast cancercells.[4] In addition to its activity at the nuclear ERs, 2-hydroxyestradiol is anantagonist of theG protein-coupled estrogen receptor (GPER) (100–1,000 μM).[5]
| Estrogen | ERTooltip Estrogen receptorRBATooltip relative binding affinity (%) | Uterine weight (%) | Uterotrophy | LHTooltip Luteinizing hormone levels (%) | SHBGTooltip Sex hormone-binding globulinRBATooltip relative binding affinity (%) |
|---|---|---|---|---|---|
| Control | – | 100 | – | 100 | – |
| Estradiol (E2) | 100 | 506 ± 20 | +++ | 12–19 | 100 |
| Estrone (E1) | 11 ± 8 | 490 ± 22 | +++ | ? | 20 |
| Estriol (E3) | 10 ± 4 | 468 ± 30 | +++ | 8–18 | 3 |
| Estetrol (E4) | 0.5 ± 0.2 | ? | Inactive | ? | 1 |
| 17α-Estradiol | 4.2 ± 0.8 | ? | ? | ? | ? |
| 2-Hydroxyestradiol | 24 ± 7 | 285 ± 8 | +b | 31–61 | 28 |
| 2-Methoxyestradiol | 0.05 ± 0.04 | 101 | Inactive | ? | 130 |
| 4-Hydroxyestradiol | 45 ± 12 | ? | ? | ? | ? |
| 4-Methoxyestradiol | 1.3 ± 0.2 | 260 | ++ | ? | 9 |
| 4-Fluoroestradiola | 180 ± 43 | ? | +++ | ? | ? |
| 2-Hydroxyestrone | 1.9 ± 0.8 | 130 ± 9 | Inactive | 110–142 | 8 |
| 2-Methoxyestrone | 0.01 ± 0.00 | 103 ± 7 | Inactive | 95–100 | 120 |
| 4-Hydroxyestrone | 11 ± 4 | 351 | ++ | 21–50 | 35 |
| 4-Methoxyestrone | 0.13 ± 0.04 | 338 | ++ | 65–92 | 12 |
| 16α-Hydroxyestrone | 2.8 ± 1.0 | 552 ± 42 | +++ | 7–24 | <0.5 |
| 2-Hydroxyestriol | 0.9 ± 0.3 | 302 | +b | ? | ? |
| 2-Methoxyestriol | 0.01 ± 0.00 | ? | Inactive | ? | 4 |
| Notes: Values are mean ± SD or range.ERRBA =Relative binding affinity toestrogen receptors of ratuterinecytosol. Uterine weight = Percentage change in uterine wet weight ofovariectomized rats after 72 hours with continuous administration of 1 μg/hour viasubcutaneously implantedosmotic pumps.LH levels =Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant.Footnotes:a =Synthetic (i.e., notendogenous).b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours).Sources:[6][7][8][9][10][11][12][13][14] | |||||
2-Hydroxyestradiol is acatechol estrogen and in this regard bears some structural resemblance to thecatecholaminesdopamine,norepinephrine (noradrenaline), andepinephrine (adrenaline).[15] In accordance, 2-hydroxyestradiol has been found to interact with catecholamine systems.[15] The steroid is known to compete with catecholamines for binding tocatechol O-methyltransferase andtyrosine hydroxylase and to directly and competitivelyinhibit theseenzymes.[15][16] In addition, 2-hydroxyestradiol has been found to displacespiperone from theD2 receptor with approximately 50% of the affinity of dopamine, whereas estradiol,estrone, andestriol and their other 2-hydroxylated and 2-methoxylated derivatives showed only weak or negligible inhibition.[15] Moreover, 2-hydroxyestradiol has been found to bind to theα1-adrenergic receptor with slightly more than half the affinity ofnorepinephrine.[17] However, although these affinities are comparable to those of dopamine and norepinephrine, they are nonetheless in the double-digitmicromolar range.[15][17]
2-Hydroxyestradiol has been found to increase prolactin secretion when administeredintravenously to women.[18] It was noted that this could be due to 2-hydroxyestradiol binding to and antagonizing the D2 receptor.[18] However, the researchers argued against this possibility because it was delayed (by several hours) and of relatively small magnitude, whereas established D2 receptor antagonists promptly induce marked increases in prolactin levels.[18] The researchers also argued against the possibility that it was due to inhibition of dopaminebiosynthesis by 2-hydroxyestradiol because2-hydroxyestrone, which inhibits tyrosine hydroxylase similarly to 2-hydroxyestradiol, showed no such increase in prolactin secretion.[18] The researchers concluded that the most likely explanation was that the increase was mediated by the estrogenic activity of 2-hydroxyestradiol, as similar increments in prolactin levels had been observed with estradiol.[18] In any case, these findings argue against the notion of major interactions of 2-hydroxyestradiol with the dopamine system.[18]
2-Hydroxyestradiol, as well as 2-hydroxyestrone and4-hydroxyestradiol, can undergo metabolicredox cycling to generatefree radicals likesuperoxide and reactive estrogensemiquinone/quinoneintermediates.[1] These metabolites may damageDNA and othercellular components.[1] However, 2-hydroxyestradiol shows little or notumorigenic activity in the male Syrian hamsterkidney and there is evidence that 2-hydroxyestradiol may actually decrease tumorigenesis in estrogen-sensitive tissues.[1] It has been suggested that the lack of tumorigenesis of 2-hydroxyestrone is due to its rapid clearance.[1] In addition, its metabolite2-methoxyestradiol is a very potent inhibitor oftumor growth andangiogenesis, and this may contribute as well.[1]
2-Hydroxyestradiol has been identified as aprodrug of2-methoxyestradiol, atransformation which is very efficiently catalyzed bycatechol O-methyltransferase in theliver.[19] 2-Methoxyestradiol is not estrogenic but is a potentangiogenesis inhibitor andagonist of theGPER with potential therapeutic implications incancer.[20]
Similarly to other steroidal estrogens, 2-hydroxyestradiol is anantioxidant, but the catechol estrogens (2- and 4-hydroxylated estrogens) like 2-hydroxyestradiol are considered to be the most potent in terms of antioxidant activity.[21][dubious –discuss]
In FENIX (fluorescence-enabled inhibited autoxidation) assays, a potentradical trapping antioxidant (RTA) activity of 2-hydroxyestradiol and 4-hydroxyestradiol was confirmed. Via this potent RTA activity, these molecules can exert a direct inhibition offerroptosis, an iron-dependent cell death.[22]
2-Hydroxyestradiol was identified as a metabolite of estradiol in 1960.[23]
