Endocrine involvement in licorice hypertension

Girerd, R. J.; Rassaert, Charles L.; DiPasquale, G.; Kroc, Robert L.

doi:10.1152/ajplegacy.1960.198.4.718

Cited by 17 publications

(5 citation statements)

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“…Although the affinity of compounds 3 and 4 for MR is unknown and the possible future studies are needed, it is estimated that the affinities would be low by the previous results of GA (Armanini et al, 1983). Indeed, there are several earlier reports (Molhuysen et al, 1950;Borst et al, 1953;Card et al, 1953;Elmadjian et al, 1956;Girerd et al, 1960) exhibiting that the adrenal gland must be present for liquorice to have mineralocorticoid activity, suggesting that glycyrrhizin and its metabolites itself including GA do not bind to MR directly in vivo. We have also addressed the capability of GA on transporting through the membrane of tubular cells, and shown that GA could not transfer into the cells under the existence of albumin (Makino et al, 2012).…”

Section: Discussionmentioning

confidence: 98%

Identification of an Alternative Glycyrrhizin Metabolite Causing Liquorice-Induced Pseudohyperaldosteronism and the Development of ELISA System to Detect the Predictive Biomarker

et al. 2021

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Liquorice is usually used as crude drug in traditional Japanese Kampo medicine and traditional Chinese medicine. Liquorice-containing glycyrrhizin (GL) can cause pseudohyperaldosteronism as a side effect. Previously, we identified 18β-glycyrrhetyl-3-O-sulfate (3) as a GL metabolite in Eisai hyperbilirubinuria rats (EHBRs) with the dysfunction of multidrug resistance-related protein (Mrp2). We speculated that 3 was associated with the onset of liquorice-induced pseudohyperaldosteronism, because it was mainly detected in serum of patients with suspected to have this condition. However, it is predicted that other metabolites might exist in the urine of EHBRs orally treated with glycyrrhetinic acid (GA). We explored other metabolites in the urine of EHBRs, and investigated the pharmacokinetic profiles of the new metabolite in EHBRs and normal Sprague-Dawley rats. We further analyzed the serum concentrations of the new metabolite in the patients of pseudohyperaldosteronism. Finally, we developed the analyzing method of these metabolites as a preventive biomarker for the onset of pseudohyperaldosteronism using an enzyme-linked immunosorbent assay (ELISA). We isolated a new GL metabolite, 18β-glycyrrhetyl-3-O-sulfate-30-O-glucuronide (4). Compound 4 significantly inhibited rat type-2 11β-hydroxysteroid dehydrogenase (11β-HSD2) and was a substrate of both organic anion transporter (OAT) 1 and OAT3. Compound 4 was also detected in the serum of patients with suspected pseudohyperaldosteronism at an approximately 10-fold lower concentrations than 3, and these concentrations were positively correlated. Compound 4 showed a lower serum concentration and weaker inhibitory titer on 11β-HSD2 than 3. We developed an enzyme-linked immunosorbent assay system using an anti-18β-glycyrrhetyl-3-O-glucuronide (3MGA) monoclonal antibody to measure the serum concentration of 3 to facilitate the measurement of biomarkers to predict the onset of pseudohyperaldosteronism. Although we found 4 as the secondary candidate causative agent, 3 could be the main potent preventive biomarker of liquorice-induced pseudohyperaldosteronism. Compound 3 was detected in serum at a higher concentration than GA and 4, implying that 3 may be a pharmacologically active ingredient mediating not only the development of pseudohyperaldosteronism but anti-inflammatory effects in humans administered GL or other liquorice-containing preparations.

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Section: Discussionmentioning

confidence: 98%

Identification of an Alternative Glycyrrhizin Metabolite Causing Liquorice-Induced Pseudohyperaldosteronism and the Development of ELISA System to Detect the Predictive Biomarker

et al. 2021

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“…However, their affinity for the receptor is significantly lower than that of the original substrate, aldosterone (4,5), and the hypothesis that it acts by directly binding to the receptor at the actual blood concentrations of GL and GA is unrealistic (1). Furthermore, previous studies found that licorice-induced PsA did not occur in patients and animals with adrenal deficiency who had lower blood cortisol levels (6)(7)(8)(9)(10).…”

Section: Pathophysiology Of Licorice-induced Psamentioning

confidence: 99%

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

et al. 2021

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Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

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“…Notably, 3,000-fold more glycyrrhetinic acid was required to achieve the same effect as aldosterone (Calò et al, 2004). Finally, neither ammoniated glycyrrhizin, nor licorice, was able to induce mineralocorticoid-like effects in adrenalized rats (Girerd et al, 1960), further indicating that direct activation of the MR by glycyrrhetinic acid is not responsible for the observed pseudo-hyperaldosteronism.…”

Section: Phytocorticoidsmentioning

confidence: 95%

Phytosteroids beyond estrogens: Regulators of reproductive and endocrine function in natural products

Dean¹,

Murphy²,

Burdette³

2017

Molecular and Cellular Endocrinology

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Foods and botanical supplements can interfere with the endocrine system through the presence of phytosteroids – chemicals that interact with steroids receptors. Phytoestrogens are well studied, but compounds such as kaempferol, apigenin, genistein, ginsenoside Rf, and glycyrrhetinic acid have been shown to interact with non-estrogen nuclear receptors. These compounds can have agonist, antagonist, or mixed agonist/antagonist activity depending on compound, receptor, cell line or tissue, and concentration. Some phytosteroids have also been shown to inhibit steroid metabolizing enzymes, resulting in biological effects through altered endogenous steroid concentrations. An interesting example, compound A (4-[1-chloro-2-(methylamino)ethyl]phenyl acetate hydrochloride (1:1)) is a promising selective glucocorticoid receptor modulator (SGRM) based on a phytosteroid isolated from Salsola tuberculatiformis Botschantzev. Given that $6.9 billion of herbal supplements are sold each year, is clear that further identification and characterization of phytosteroids is needed to ensure the safe and effective use of botanical supplements.

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Endocrine involvement in licorice hypertension

Cited by 17 publications

References 0 publications

Identification of an Alternative Glycyrrhizin Metabolite Causing Liquorice-Induced Pseudohyperaldosteronism and the Development of ELISA System to Detect the Predictive Biomarker

Identification of an Alternative Glycyrrhizin Metabolite Causing Liquorice-Induced Pseudohyperaldosteronism and the Development of ELISA System to Detect the Predictive Biomarker

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

Phytosteroids beyond estrogens: Regulators of reproductive and endocrine function in natural products

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