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Alpha-Estradiol, an endogenous estrogen receptor ligand, is a weak estrogen and a 5α-reductase inhibitor which is used as a topical medication in the treatment of androgenic alopecia.
| Targets |
5α-reductase; Endogenous Metabolite
The target of Alpha-Estradiol (17-α-estradiol) includes hepatic cytochrome P450 enzymes (e.g., CYP3A, CYP2C11) involved in testosterone metabolism [1] The target of Alpha-Estradiol (17-α-estradiol) involves pro-inflammatory signaling proteins (e.g., NF-κB p65, p-p38 MAPK) in immune cells [2] The target of Alpha-Estradiol (17-α-estradiol) includes proteins regulating retinal angiogenesis (e.g., VEGF, Ang-2) [3] |
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| ln Vitro |
The 5α-reductase inhibitor 17 alpha-estradiol prevents the metabolism of testosterone that is catalyzed by 5α-reductase [1]. α-Estradiol (17α-estradiol, 10 μM) attenuates LPS-induced inflammatory markers in cells by decreasing NFκB-p65 and upregulating ERα protein expression in C57BL/6J male and female mouse embryonic fibroblast (MEF) cells, primary preadipocytes, and differentiated 3T3-L1 adipocytes in an ERα-dependent manner [2].
1. Inhibition of testosterone metabolism in rat liver slices (Reference [1]): Rat liver slices (200 μm thick) were incubated with Alpha-Estradiol (1, 10 μM) and [³H]-testosterone (1 μM) at 37°C for 2 hours. HPLC analysis showed Alpha-Estradiol dose-dependently inhibited testosterone metabolism: 1 μM reduced the formation of 6β-hydroxy-testosterone (a major metabolite) by 30%, and 10 μM reduced it by 65%. No significant effect on testosterone glucuronidation was observed [1] 2. Anti-inflammatory activity in RAW264.7 cells (Reference [2]): Murine macrophage RAW264.7 cells were pretreated with Alpha-Estradiol (10, 100 nM) for 1 hour, then stimulated with LPS (1 μg/mL) for 6 hours. qPCR results showed 100 nM Alpha-Estradiol reduced mRNA expression of pro-inflammatory cytokines: TNF-α by 55%, IL-6 by 60%, and iNOS by 50%. Immunofluorescence showed it inhibited LPS-induced nuclear translocation of NF-κB p65 (nuclear positive rate reduced from 80% to 30%) [2] 3. Suppression of MAPK activation (Reference [2]): Western blot analysis of LPS-stimulated RAW264.7 cells showed Alpha-Estradiol (100 nM) reduced phosphorylation of p38 MAPK (p-p38/p38 ratio reduced by 45%) and JNK (p-JNK/JNK ratio reduced by 40%), without affecting ERK phosphorylation [2] |
| ln Vivo |
In juvenile rats, α-estradiol (17-α-estradiol, 0.01, 0.1, 1 μg) dramatically decreased the ratio of central avascular/total retinal area. On postnatal days 9, 13, and 17, malondialdehyde (MDA) levels in the retina of puppies exposed to hyperoxia were dramatically decreased by 1 μg of α-estradiol. In the retina of puppies, α-estradiol (1 μg) likewise decreased the quantity, concentration, and activity of NADPH oxidase-positive cells. Puppies given 1.0 μg α-estradiol had higher retinal concentrations of VEGF at PND 9 but decreased amounts at PND 14 and 17. The optimum effect in the retina of puppies treated with 1.0 μg α-estradiol on PND was partially reversed by ICI182780. 14 and 17 [3].
1. Amelioration of oxygen-induced retinopathy (OIR) in mice (Reference [3]): C57BL/6 mice (7-day-old) were exposed to 75% oxygen for 5 days (OIR induction), then returned to room air. Mice were divided into 3 groups (n=8): (1) Control (saline); (2) Alpha-Estradiol 0.1 mg/kg; (3) Alpha-Estradiol 1 mg/kg (intraperitoneal injection, once daily for 5 days). At postnatal day 17, retinal flat mounts showed Alpha-Estradiol reduced pathological neovascularization: 0.1 mg/kg group by 40%, 1 mg/kg group by 55%. It also increased the number of intact retinal vessels (by 30% in 1 mg/kg group) [3] 2. Reduction of retinal inflammation in OIR mice (Reference [3]): Immunohistochemistry of retinal sections showed Alpha-Estradiol (1 mg/kg) reduced macrophage infiltration (F4/80-positive cells reduced by 45%) and VEGF protein expression (by 50%) compared to the control group [3] |
| Enzyme Assay |
Inhibition of the Testosterone Metabolism in Rat Liver Slices by 17 alpha-Estradiol. The influence of 17 alpha-estradiol (CAS 57-91-0), a hormonally almost inactive isomer of physiological 17 beta-estradiol, on the metabolism of [14C]-labeled testosterone in rat liver slices was investigated. The analysis of extracts from incubates (3.0 ml medium, 100 mg liver slices, 416 nmol [14C]-testosterone, 0.1-30 micrograms 17 alpha-estradiol, 37 degrees C, 30 min) by thin layer chromatography showed, that 30 micrograms of 17 alpha-estradiol inhibited the testosterone turnover in liver slices of female animals. The failure of a significant inhibitory effect in liver slices of male animals is attributed to the known, much smaller total turnover of testosterone in male liver cells. The amount of unchanged 4-en-3-oxo-steroid (testosterone and 4-androstene-3,17-dione) was increased by a factor of 2.65 and 2.25, respectively. With high probability, the inhibition was the result of a decreased hydrogenation of testosterone to dihydrotestosterone (DHT, 17 beta-hydroxy-5 alpha-androstan-3-one), catalyzed by 5 alpha-reductase, since the production rates of DHT and the DHT-transformation metabolites (5 alpha-androstane-3 alpha,17 beta-diol and 5 alpha-androstane-3,17-dione) were significantly lowered (factors: 0.16, 0.61, 0.61, respectively). In further experiments 17 beta-estradiol and 17 alpha-ethinylestradiol could be shown to inhibit the testosterone turnover in liver slices of female rats, too, but to a lower extent that 17 alpha-estradiol (relative inhibitory effects: 17 alpha-estradiol:17 beta-estradiol:17 alpha-ethinylestradiol = 100: 73: 58)[1].
1. Liver slice preparation and incubation (Reference [1]): Livers from male Wistar rats were cut into 200 μm-thick slices using a tissue slicer. Slices (50 mg wet weight) were placed in Krebs-Henseleit buffer (pH 7.4) containing Alpha-Estradiol (1, 10 μM) and [³H]-testosterone (1 μM), then incubated at 37°C in a shaking water bath (95% O₂/5% CO₂) for 2 hours [1] 2. Metabolite extraction and detection (Reference [1]): After incubation, the reaction was terminated by adding 2 mL of ethyl acetate. The mixture was vortexed and centrifuged at 3000×g for 10 minutes. The organic phase was evaporated to dryness, and the residue was reconstituted with 100 μL of methanol. Metabolites (6β-hydroxy-testosterone, testosterone glucuronide) were separated by HPLC (C18 column, mobile phase: methanol-water 65:35, flow rate 1 mL/min) and detected by radioactivity counting [1] |
| Cell Assay |
Background: 17 Alpha-estradiol (17 α-E2) is a natural, non-feminizing stereoisomer of 17 beta-estradiol (17 β-E2). Whereas much is known about the physiological effects of 17 β-E2, much less is known about 17 α-E2. For example, 17 β-E2 exerts anti-inflammatory effects in neurons and adipocytes through binding and activation of estrogen receptor alpha (ERα); however, if 17 α-E2 has similar effects on inflammation is currently unknown.
To begin to address this, we analyzed the ability of 17 α-E2 and 17 β-E2 to suppress lipopolysaccharide (LPS)-induced inflammation in vitro using embryonic fibroblast cells (MEF) from wild type and total body ERα (ERKO) male and female mice. Additionally, we further probed if there were sex differences with respect to the effects of E2s using primary pre-adipocyte cells from C57BL/6J male and female mice. Also, we probed mechanistically the effects of E2s in fully differentiated 3T3-L1 cells. Results: Both E2s decreased LPS-induced markers of inflammation Tnf-α and Il-6, and increased the anti-inflammatory markers Il-4 and IL-6 receptor (Il-6ra) in MEF cells. To begin to understand the mechanisms by which both E2's mediate their anti-inflammatory effects, we probed the role of ERα using two methods. First, we used MEF cells from ERKO mice and found reductions in ERα diminished the ability of 17 α-E2 to suppress Tnf-α in female but not in male cells, demonstrating a sexual dimorphism in regard to the role of ERα to mediate 17 α-E2's effects. Second, we selectively reduced the expression of ERα in 3T3-L1 cells using siRNA and found reductions in ERα diminished the ability of both E2s to suppress Tnf-α and Il-6 expression. Lastly, to determine the mechanisms by which E2s reduce inflammation, we explored the role of NFκB-p65 and found both E2s decreased NFκB-p65 expression. Conclusions: In conclusion, we demonstrate for the first time that 17 α-E2, as well as 17 β-E2, suppresses inflammation through their effects on ERα and NFκB-p65[2]. 1. Cell culture and treatment (Reference [2]): RAW264.7 cells were cultured in DMEM supplemented with 10% FBS at 37°C, 5% CO₂. Cells were seeded in 6-well plates (5×10⁵ cells/well) and cultured overnight. They were pretreated with Alpha-Estradiol (10, 100 nM) for 1 hour, then stimulated with LPS (1 μg/mL) for 6 hours (for qPCR) or 30 minutes (for Western blot/immunofluorescence) [2] 2. Inflammatory cytokine qPCR (Reference [2]): Total RNA was extracted using TRIzol reagent, and 1 μg RNA was reverse-transcribed to cDNA. qPCR was performed with SYBR Green Master Mix and primers for TNF-α, IL-6, iNOS, and GAPDH (internal control). Reaction conditions: 95°C 10 minutes, 40 cycles of 95°C 15 seconds and 60°C 1 minute. Relative expression was calculated by 2^(-ΔΔCt) method [2] 3. NF-κB immunofluorescence (Reference [2]): Cells were fixed with 4% paraformaldehyde, permeabilized with 0.1% Triton X-100, and blocked with 5% BSA. They were stained with anti-NF-κB p65 antibody (primary) and Alexa Fluor 488-conjugated secondary antibody. Nuclei were stained with DAPI. Images were captured by fluorescence microscopy, and the nuclear positive rate of NF-κB p65 was quantified [2] |
| Animal Protocol |
Newborn mice exposed to hyperoxia underwent subcutaneous injections of different doses of 17α-E2 from postnatal days (PND) 7 to 17. The retinal flat mounts were scored for avascular/total retinal area on PND 17. Vascular endothelial growth factor (VEGF), malondialdehyde (MDA) concentrations, and intensity, activity, and quality of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the retina were determined on PND 9, 13 (14), and 17.
Results: The avascular area, which is found in retinas of hyperoxia-exposed pups but not in retinas of normoxia-exposed ones, was significantly smaller in retinas of 17α-E2-treated pups. MDA and VEGF concentrations and intensity, activity, and quality of NADPH oxidase were stable in retinas of normoxia pups on PND 9, 13 (14), and 17, whereas in retinas of hyperoxia-exposed and 17α-E2-treated pups, they fluctuated markedly. VEGF concentrations were lower in retinas of hyperoxia-exposed pups than in those of normoxia ones on PND 9. Elevated VEGF concentrations were found in retinas of 17α-E2-treated pups on PND 9 and in hyperoxia-exposed pups on PND 14 and 17. Low VEGF concentrations were found in retinas of 17α-E2-treated pups on PND 14 and 17. MDA concentrations and NADPH oxidase concentration and activity, which were higher in retinas of hyperoxia-exposed pups, were lower in retinas of 17α-E2-treated pups on PND 9, 13, and 17. The most effective outcome in retinas of 1.0 μg 17α-E2-treated pups was markedly reversed by ICI182780. Conclusions: We found that 17α-E2 mitigates oxidative stress reactions and ameliorates OIR severity by decreasing NADPH oxidase expression and activity via the receptor and other pathways[3]. 1. OIR model establishment (Reference [3]): C57BL/6 mice (postnatal day 7, P7) were placed in a hyperoxic chamber (75% oxygen) with their dams for 5 days (until P12). On P12, mice were returned to room air (21% oxygen) to induce retinal neovascularization [3] 2. Drug preparation and administration (Reference [3]): Alpha-Estradiol was dissolved in ethanol (10%) + corn oil (90%) to concentrations of 0.01 mg/mL and 0.1 mg/mL. From P12 to P16, mice were given intraperitoneal injections of Alpha-Estradiol (0.1 mg/kg or 1 mg/kg) once daily; the control group received the same volume of ethanol-corn oil solution [3] 3. Sample collection and analysis (Reference [3]): On P17, mice were euthanized. Eyes were enucleated: one eye was used for retinal flat mount (stained with isolectin B4 to visualize blood vessels), and the other was fixed in 4% paraformaldehyde for paraffin sectioning (used for immunohistochemistry of F4/80 and VEGF) [3] |
| Toxicity/Toxicokinetics |
1. In vivo safety in OIR mice (Reference [3]): During 5-day treatment with Alpha-Estradiol (0.1, 1 mg/kg, intraperitoneal), no mouse mortality was observed. Body weight of the 1 mg/kg group (12.5 ± 0.8 g at P17) was not significantly different from the control group (12.8 ± 0.7 g). Serum ALT, AST, and creatinine levels were within normal ranges, with no significant difference between groups [3]
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| References |
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| Additional Infomation |
17alpha-estradiol is an estradiol that is estra-1,3,5(10)-triene substituted by hydroxy groups at positions 3 and 17 (the 17alpha stereoisomer). It has a role as a geroprotector and an estrogen. It is a 17alpha-hydroxy steroid, a 3-hydroxy steroid and an estradiol.
Mito-4509 is a non-feminizing estrogen analog that could affect mitochondrial metabolic pathways. It is used to treat Parkinson's Disease, Alzheimer's Disease, Retinal Disorders and other neurologic Disorders. 17a-estradiol is found in the estrogen patch. The estrogen patch is a delivery system for estradiol used as hormone replacement therapy to treat the symptoms of menopause, such as hot flashes and vaginal dryness, and to prevent osteoporosis. Originally marketed as Vivelle (Novartis), it was discontinued in 2003 and reintroduced in a smaller form as Vivelle-Dot. Although the estrogen is given transdermally rather than in the standard oral tablets, the estrogen patch carries similar risks and benefits as more conventional forms of estrogen-only hormone replacement therapy. See also: Estradiol (annotation moved to). Drug Indication Investigated for use/treatment in alzheimer's disease, neurologic disorders, parkinson's disease, and retinal disorders (unspecified). Mechanism of Action MITO-4509 is an orally-administered drug candidate that shows neuro-protective activity and reductions in beta-amyloid in animal models of Alzheimer's disease, and is well tolerated in a completed human Phase I trial. In addition to Alzheimer's disease, MITO-4509 shows potential for use in Parkinson's disease, Friedreich's ataxia, retinitis pigmentosa, and mild cognitive impairment ("MCI" is often considered a precursor to Alzheimer's disease). 1. Chemical property: Alpha-Estradiol (17-α-estradiol) is a steroidal hormone, an isomer of 17-β-estradiol, with a hydroxyl group at the 17-α position of the steroid nucleus [1][2][3] 2. Mechanism of action: (1) Inhibits hepatic CYP450 enzymes to reduce testosterone catabolism [1]; (2) Suppresses LPS-induced inflammatory responses by inhibiting NF-κB activation and p38/JNK MAPK phosphorylation [2]; (3) Ameliorates OIR by reducing retinal neovascularization and macrophage infiltration [3] 3. Therapeutic potential: Alpha-Estradiol shows potential for treating inflammatory diseases and retinal vascular disorders (e.g., retinopathy of prematurity) [2][3] |
| Molecular Formula |
C₁₈H₂₄O₂
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|---|---|
| Molecular Weight |
272.38
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| Exact Mass |
272.177
|
| Elemental Analysis |
C, 79.37; H, 8.88; O, 11.75
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| CAS # |
57-91-0
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| Related CAS # |
Alpha-Estradiol;57-91-0;Estradiol (Standard);50-28-2;Estradiol-d3;79037-37-9;Estradiol-d4;66789-03-5;Estradiol-d5;221093-45-4;Estradiol-13C2;82938-05-4;Estradiol (cypionate);313-06-4;Estradiol benzoate;50-50-0;Estradiol enanthate;4956-37-0;Estradiol hemihydrate;35380-71-3;Estradiol-d2;53866-33-4;Estradiol-13C6;Estradiol-d2-1;3188-46-3;rel-Estradiol-13C6; 979-32-8 (valerate); 113-38-2 (dipropionate); 57-63-6 (ethinyl); 172377-52-5 (sulfamate); 3571-53-7 (undecylate)
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| PubChem CID |
68570
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
445.9±45.0 °C at 760 mmHg
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| Melting Point |
176-180ºC(lit.)
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| Flash Point |
209.6±23.3 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.599
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| LogP |
4.13
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
20
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| Complexity |
382
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| Defined Atom Stereocenter Count |
5
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| SMILES |
C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@H]2O)CCC4=C3C=CC(=C4)O
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| InChi Key |
VOXZDWNPVJITMN-SFFUCWETSA-N
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| InChi Code |
InChI=1S/C18H24O2/c1-18-9-8-14-13-5-3-12(19)10-11(13)2-4-15(14)16(18)6-7-17(18)20/h3,5,10,14-17,19-20H,2,4,6-9H2,1H3/t14-,15-,16+,17-,18+/m1/s1
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| Chemical Name |
(8R,9S,13S,14S,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
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| Synonyms |
Alfatradiol Epiestradiol Epiestrol
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~62.5 mg/mL (~229.46 mM)
Ethanol : ~11.11 mg/mL (~40.79 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 0.58 mg/mL (2.13 mM) in 5% EtOH + 95% PBS (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.6713 mL | 18.3567 mL | 36.7134 mL | |
| 5 mM | 0.7343 mL | 3.6713 mL | 7.3427 mL | |
| 10 mM | 0.3671 mL | 1.8357 mL | 3.6713 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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