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Glycyrrhetic Acid 3-O-β-D-Glucuronide is natural product of the triterpenoid class. It is isolated from glycyrrhiza and is an important derivative of glycyrrhizin (GL) with an anti -allergic activity. Glycyrrhetic acid 3-O-β-D-glucuronide (GAMG) shows that β‐glucuronidases (β‐GUS) are key GAMG-producing enzymes, displaying a high potential to convert GL directly into GAMG.Glycyrrhetic acid 3-O-β-D-glucuronide is valuable as a sweetener.
| ln Vitro |
β-hexosaminidase release from RBL-2H3 cells can be inhibited by glycyrrhetinic acid 3-O-β-D-glucuronide, with an IC50 value of 0.28 mM[2]. With an IC50 value of 120 μM, glycyrrhetinic acid 3-O-β-D-glucuronide (GAMG) considerably lowers the nitrite concentration in LPS-induced RAW264.7 cells in a dose-dependent manner [2].
GAMG inhibited the release of β-hexosaminidase from RBL-2H3 cells induced by IgE with an IC50 value of 0.28 mM. GL and GA showed IC50 values of 0.37 mM and 0.23 mM, respectively. The reference drug disodium cromoglycate (DSCG) had an IC50 of 0.50 mM [1]. GAMG inhibited nitric oxide (NO) production in LPS-induced RAW264.7 cells with an IC50 value of 0.12 mM. GL, GA, and dexamethasone showed IC50 values of 0.09 mM, 0.05 mM, and 0.01 mM, respectively [1]. GAMG did not show any antioxidant activity in DPPH free radical and superoxide radical generation systems [1]. 18α-GAMG exhibited higher antiproliferative activity against human liver cancer SMMC-7721 and gastric cancer MGC-803 cells than the positive control doxorubicin. It influenced cell-cycle arrest and downregulated the expression of protein p65 and hTERT. 18α-GAMG showed no toxic effect on human normal gastric mucosa cell GES-01 and normal liver cell L-02 (IC50 = 3.0 mM for both) [2]. 18α-GAMG has stronger EGFR inhibitory activity than GLs and erlotinib, with higher binding affinity to EGFR as shown by molecular docking (six hydrogen bonds with ASP831, GLU738, THR766, LYS721 and a charge interaction with LYS692 for 18α-GAMG; three hydrogen bonds and three charge interactions for 18β-GAMG) [2]. |
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| ln Vivo |
GAMG administered intraperitoneally (i.p.) at 5 mg/kg inhibited the passive cutaneous anaphylaxis (PCA) reaction in mice by 42.7±1.2%. Orally administered (p.o.) at 5 mg/kg inhibited by 28.5±3.1%. GA (i.p. 5 mg/kg) showed 61.0±1.5% inhibition, while DSCG (p.o. 50 mg/kg) showed 38±0.2% and azelastine (5 mg/kg) showed 70.0±5.6% (i.p.) and 71.5±4.3% (p.o.) [1].
In the oxazolone-induced contact hypersensitivity model, GAMG (1% applied to mouse ear) did not inhibit ear thickness increase. GL also showed no inhibition. GA exhibited weak inhibitory activity, and dexamethasone showed potent inhibition [1]. GAMGs (18α-GAMG and 18β-GAMG) showed higher inhibition against tumor growth on S180 and HepG2 xenograft mice and longer survival time against EAC-bearing mice than GLs [2]. 18α-GAMG improved pathological changes of DEN-induced rat hepatic tumor by downregulating the expression of protein p65 and hTERT and blocking excessive proliferation of tumor cells [2]. 18α-GAMG improved pathological changes of CCl4-related hepatic fibrosis by blocking the activation of NF-κB and MAPKs signaling pathways [2]. |
| Cell Assay |
RBL-2H3 cell degranulation assay: RBL-2H3 cells were grown in DMEM supplemented with 10% fetal bovine serum and L-glutamine. Cells were dispensed into 24-well plates at 5×10^5 cells per well in medium containing 0.5 μg/mL mouse monoclonal IgE and incubated overnight at 37°C in 5% CO2 for sensitization. Cells were washed with siraganian buffer (pH 7.2: 119 mM NaCl, 5 mM KCl, 0.4 mM MgCl2, 25 mM PIPES, 40 mM NaOH) and then incubated in 160 μL of siraganian buffer (supplemented with 5.6 mM glucose, 1 mM CaCl2, 0.1% BSA) for 10 min at 37°C. Cells were exposed to 40 μL of test compounds for 20 min, followed by treatment with 20 μL of antigen (DNP-HSA, 1 μg/mL) for 10 min at 37°C to induce degranulation. Reaction was quenched on ice for 10 min. After centrifugation, 25 μL of supernatant was transferred to 96-well plates and incubated with 20 μL of substrate (1 mM p-nitrophenyl-N-acetyl-β-D-glucosaminide) for 1 h at 37°C. Reaction was stopped by adding 0.2 mL NaOH, and absorbance was measured at 405 nm [1].
NO production assay in RAW264.7 cells: RAW264.7 cells were stimulated with LPS (1 μg/mL) and test compounds for 24 h. Cells were briefly centrifuged, and 150 μL of cell culture supernatant was mixed with 150 μL of Griess reagent, then incubated for 5-10 min at room temperature protected from light. Absorbance was measured at 540 nm using an ELISA reader against a sodium nitrate standard curve [1]. Antiproliferative activity assay (from review): Human tumor cell lines (HepG2, HeLa, A549) were used to evaluate antiproliferative activities. EGFR inhibitory activity was measured. Molecular docking was performed to analyze binding interactions between GAMGs and the EGFR active site (PDB ID 1M17) [2]. |
| Animal Protocol |
Passive cutaneous anaphylaxis (PCA): Male ICR mice (25-30 g) were intradermally injected with 10 μg of anti-DNP IgE into each of two dorsal skin sites that had been shaved 48 h earlier. Sites were outlined with a water-insoluble red marker. After 48 h, each mouse was intravenously injected via the tail vein with 200 μL of 3% Evans blue PBS containing 200 μg of DNP-HSA. Test compounds (GAMG, GL, GA, DSCG, azelastine) were administered orally (p.o.) or intraperitoneally (i.p.) at indicated doses (e.g., 5 mg/kg for GAMG, GL, GA; 50 mg/kg for DSCG; 5 mg/kg for azelastine) 1 h prior to DNP-HSA challenge. Thirty minutes after antigen injection, mice were sacrificed and dorsal skins removed. Dye was extracted with 1 mL of 1.0 N KOH and 4 mL of acetone/0.6 N phosphoric acid (13:5), and absorbance was measured at 620 nm [1].
Contact hypersensitivity (oxazolone-induced dermatitis): Female ICR mice (25-28 g) were sensitized by applying 100 μL of 1.5% oxazolone in ethanol to the abdomen. Starting 7 days after sensitization, 20 μL of 1% oxazolone in acetone/olive oil (4:1) was applied to both sides of the ear every 3 days. GAMG, GL, or GA was applied at 1% concentration in a total volume of 20 μL to both sides of the ear 30 min before and 3 h after each oxazolone application. Ear thickness was measured using a Digimatic Micrometer at 72 h after each oxazolone application [1]. Tumor xenograft models (from review): Sarcoma cells S180, hepatoma cells HepG2, and Ehrlich ascites cells EAC were used in mice. Inhibitory rate against tumor growth and survival time were determined [2]. DEN-induced rat hepatic tumor model (from review): Microscopic features were examined after administration of 18α-GAMG [2]. |
| ADME/Pharmacokinetics |
When GL is orally administered to humans, it is mainly metabolized to GA by intestinal bacteria, and to a minor extent to GA via GAMG. GAMG is quickly metabolized to GA rather than to GL [1].
GL is absorbed from the stomach and partially (about 40%) converted to GAMG within gastric epithelial cells, then completely metabolized to GAMG in the liver, excreted via the bile duct, and metabolized to GA by intestinal bacteria. GA and its metabolites are transferred to the liver from the intestinal tract [2]. The transport of GL and GAMG across cell membranes: GAMG has suitable molecular polarity enabling it to pass through both hydrophobic and hydrophilic cell membranes, resulting in increased bioavailability and bioactivities compared to GL [2]. |
| References |
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| Additional Infomation |
Glycyrrhetinic acid 3-O-glucuronide is a triterpenoid saponin, specifically the 3-O-β-glucuronide of glycyrrhetinic acid. It is a metabolite of glycyrrhizic acid in licorice and may be a pathogenic factor in the pathogenesis of pseudoaldosteronism. It possesses various functions, including anti-allergic activity, sweetness, EC 1.1.1.146 (11β-hydroxysteroid dehydrogenase) inhibitor, human xenobiotic metabolite, and plant metabolite. It is a monosaccharide derivative, β-D-glucuronic acid, triterpenoid saponin, pentacyclic triterpenoid, oxodicarboxylic acid, and enone. Its functions are related to glycyrrhetinic acid.
GAMG is sweeter than GL. The intensity of sweetness of GAMG is 940 times that of sucrose, while GL is 170 times that of sucrose [2]. GAMG may be useful as a new food additive as well as an anti-allergic agent [1]. GAMG has higher solubility and better taste (less aftertaste) than GL. It can be blended with organic acid salts or 5% salt solution to increase water solubility and sweetening power [2]. In Japan, enzymatically modified licorice extract containing GAMG is used as a sweetener in foods such as chocolate, ice cream, cocoa, coffee, soups, and milk products. A mixture of GAMG and GL (3:7) is used for salt-containing foods like soy sauce [2]. GAMG can also be used as an emulsifier or solubilization agent in cosmetic products [2]. The anti-allergic mechanism of GAMG involves inhibition of β-hexosaminidase release from mast cells and inhibition of NO production in LPS-induced macrophages, but not via antioxidant activity [1]. 18α-GAMG exerts anti-inflammatory activity by blocking NF-κB and MAPKs signaling pathways [2]. |
| Molecular Formula |
C36H54O10
|
|---|---|
| Molecular Weight |
646.8080
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| Exact Mass |
646.372
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| CAS # |
34096-83-8
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| PubChem CID |
161800
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| Appearance |
White to off-white solid
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| Density |
1.31g/cm3
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| Boiling Point |
785ºC at 760mmHg
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| Flash Point |
240.7ºC
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| LogP |
4.329
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
|
| Heavy Atom Count |
46
|
| Complexity |
1340
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| Defined Atom Stereocenter Count |
14
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| SMILES |
O([C@@]1([H])[C@@]([H])([C@]([H])([C@@]([H])([C@@]([H])(C(=O)O[H])O1)O[H])O[H])O[H])[C@@]1([H])C([H])([H])C([H])([H])[C@@]2(C([H])([H])[H])[C@@]([H])(C([H])([H])C([H])([H])[C@@]3(C([H])([H])[H])[C@]4(C([H])([H])[H])C([H])([H])C([H])([H])[C@@]5(C([H])([H])[H])C([H])([H])C([H])([H])[C@@](C(=O)O[H])(C([H])([H])[H])C([H])([H])[C@@]5([H])C4=C([H])C([C@@]32[H])=O)C1(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
HLDYLAJAWSKPFZ-QDPIGISRSA-N
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| InChi Code |
InChI=1S/C36H54O10/c1-31(2)21-8-11-36(7)27(34(21,5)10-9-22(31)45-29-25(40)23(38)24(39)26(46-29)28(41)42)20(37)16-18-19-17-33(4,30(43)44)13-12-32(19,3)14-15-35(18,36)6/h16,19,21-27,29,38-40H,8-15,17H2,1-7H3,(H,41,42)(H,43,44)/t19-,21-,22-,23-,24-,25+,26-,27+,29+,32+,33-,34-,35+,36+/m0/s1
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| Chemical Name |
(2S,3S,4S,5R,6R)-6-[[(3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
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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 : ~250 mg/mL (~386.51 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.22 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.22 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5460 mL | 7.7302 mL | 15.4605 mL | |
| 5 mM | 0.3092 mL | 1.5460 mL | 3.0921 mL | |
| 10 mM | 0.1546 mL | 0.7730 mL | 1.5460 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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