Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study

Takahashi, Kanon; Yoshino, Tetsuhiro; Maki, Yasuhito; Ishiuchi, Kan’ichiro; Namiki, Takao; Ogawa‐Ochiai, Keiko; Minamizawa, Kiyoshi; Makino, Toshiaki; Nakamura, Tomonori; Mimura, Masaru; Watanabe, Kenji

doi:10.1007/s00204-019-02588-2

Cited by 23 publications

(30 citation statements)

References 25 publications

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“…Orally administered GL is hydrolysed by intestinal bacteria to GA and appears in circulating blood (Akao et al, 1994). GA then translocates to the liver where it is metabolised to compounds 1-3, and 18β-glycyrrhetyl-3-O-glucuronide (6, 3MGA; Figure 1A) by sulfotransferase (SULT) 2A1 (Takahashi et al, 2019), some cytochrome P450 (CYP) enzymes, and some glucuronyltransferases (Kato et al, 1995;Makino et al, 2008;Makino et al, 2012;Morinaga et al, 2018;Ishiuchi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Kambakutaisoto includes relatively higher amounts of Chinese licorice, raising concerns for pseudoaldosteronism. 20 The primary symptoms of pseudoaldosteronism are hypokalemia and body weight gain. Thus, these parameters were compared before and after initiating kambakutaisoto.…”

Section: Resultsmentioning

confidence: 99%

Kambakutaisoto Treatment for Children With Night Crying and Arousal Parasomnias Developed During Prolonged Hospitalization for Hematological and Oncological Diseases

Kawashima

2021

J Child Neurol

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Objective: The lack of an established treatment standard prompted an examination of whether kambakutaisoto, an herbal formula, is effective for non–rapid eye movement (NREM)–related parasomnias and night crying (provisionally defined as an infantile form of arousal parasomnia). Methods: This study included 137 children aged median 4.1 years (range, 0.02–18.5) who were admitted for hematological and oncological diseases. Results: Of 137, 3 children developed recurrent episodes of NREM-related parasomnias, and 3 developed night crying. The proportion of children with night-crying/parasomnia receiving invasive procedures was significantly higher than those without (100% vs. 47%, P = .013). All 6 children with night crying/parasomnia received kambakutaisoto at a dose of 0.13–0.22 g/kg per os and responded from the start of administration with a significant reduction in the number of episodes. No adverse effects were observed. Conclusion: Kambakutaisoto may be a safe and promising therapy for night crying and NREM-related parasomnias in children.

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“…In addition, GA cannot be transferred to renal tubular epithelial cells because the most of GA is bound to albumin in the blood, but during hypoalbuminemia, the concentration of free GA may increases and transport into tubular cells by passive diffusion to inhibit 11βHSD2 [19,20]. On the other hand, the concentration of urinary compound 3 in patient samples was lower than that in blood concentration [17]. Therefore, it is undeniable that unknown GL metabolites that could not be detected may exist in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Compound 3 was produced from GA in the human liver cytosol fraction with a Km value (Michaelis constant) of 0.61 ± 0.44 μM (mean ± S.E., repeated four times) based on Hanes-Woolf plots. GA was not metabolised to compound 3 by SULT1A1 and 2B1, but SULT2A1 metabolised GA with a Km value of 0.73 ± 0.28 μM (mean ± S.E., repeated four times) [17].…”

Section: Pharmacokinetics Of Compounds 1-3 and Their Possibilities As The Causative Compounds For Pseudoaldosteronismmentioning

confidence: 96%

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Exploration for the real causative agents of licorice-induced pseudoaldosteronism

Makino

2021

J Nat Med

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I investigated the causative agents of licorice-induced pseudoaldosteronism, which is a frequent side effect of Japanese traditional Kampo medicines. Glycyrrhizin (GL), the main ingredient of licorice, is absorbed after being metabolized to glycyrrhetinic acid (GA) by intestinal bacteria, and then metabolized in liver to 3-monoglucuronyl-glycyrrhetinic acid (3MGA). In normal condition, 3MGA is excreted into bile via a multidrug resistance-related protein (Mrp) 2, therefore, 3MGA does not appear in blood circulation. However, under the dysfunction of Mrp2, 3MGA appears in the blood circulation and is excreted into the urine by not glomerular filtration but tubular secretion via organic anion transporter (OAT) 1 and 3. At this time, 3MGA inhibits type 2 11β-hydroxysteroid dehydrogenase (11βHSD2) in tubular cells to cause pseudoaldosteronism. Since GA is not the substrates of these transporters, GA cannot inhibit 11βHSD2 in tubular cells. Therefore, it was considered that 3MGA was the causative agents of licorice-induced pseudoaldosteronism. After that, I isolated and identified three other GL metabolites, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate (2), and 18β-glycyrrhetyl-3-O-sulfate (3) from the urine of Mrp2-deficient rats orally treated with GA, and found that their blood and urinary concentrations were much higher than 3MGA and that their pharmacokinetic behaviors were similar to 3MGA. 3MGA was not detected in the blood of patients with pseudoaldosteronism who developed rhabdomyolysis due to licorice, and compound 3 was detected at a high concentration. In addition, a multicenter retrospective study was conducted using the serum and urine of 97 patients who took Kampo medicines containing licorice. Of a total of 97 patients, 67 detected GA in the serum (median 122 nM, 5 nM–1.8 µM) and 68 detected compound 3 (median 239 nM, 2 nM–4.2 µM), and there were no cases of detection of GL, 3MGA, compounds 1, and 2. High blood concentrations of compound 3 were associated with low plasma renin activity, plasma aldosterone levels, and serum potassium levels. It is highly probable that compound 3 is the true causative agent of pseudoaldosteronism.

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Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study

Cited by 23 publications

References 25 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

Kambakutaisoto Treatment for Children With Night Crying and Arousal Parasomnias Developed During Prolonged Hospitalization for Hematological and Oncological Diseases

Exploration for the real causative agents of licorice-induced pseudoaldosteronism

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