Analysis of clinical factors associated with Kampo formula-induced pseudoaldosteronism based on self-reported information from the Japanese Adverse Drug Event Report database.

Drug-induced pseudoaldosteronism is a typical adverse effect of Kampo formulas. Previous research described the potential risks of Kampo formula-linked pseudoaldosteronism. However, few studies assessed the risk factors using a real-world database and a data-mining approach. Using the Japanese Adverse Drug Event Report database, we extracted pseudoaldosteronism reports for 148 Kampo formulas covered by Japanese national health insurance. Adverse events were decided according to the preferred terminology of the Medical Dictionary for Regulatory Activities/Japanese version 25.1. We calculated reporting odds ratio (RORs) and identified Kampo formulas as suspected causes of pseudoaldosteronism. Moreover, we evaluated clinical factors associated with Kampo formula-induced pseudoaldosteronism via logistic regression. From April 2004 to November 2022, 6334 adverse events related to the Kampo formulas were reported. We selected 2471 reports containing complete clinical data, including 210 reports on pseudoaldosteronism. In the pseudoaldosteronism group, 69.0% of patients were female, and 85.2% were ≥70 years old. The formulas most commonly associated with pseudoaldosteronism were Shakuyakukanzoto, Yokukansan, and Ryokeijutsukanto (ROR [95% confidence interval {CI}] = 18.3 [13.0-25.9], 8.1 [5.4-12.0], and 5.5 [1.4-21.9], respectively). Logistic analysis identified female sex (odds ratio [OR] [95% CI] = 1.7 [1.2-2.6]; P = 0.006), older age (≥70, 5.0 [3.2-7.8]; P < 0.001), low body weight (<50 kg, 2.2 [1.5-3.2]; P < 0.001), diuretics usage (2.1 [1.3-4.8]; P = 0.004), hypertension (1.6 [1.1-2.4]; P = 0.014), and dementia (7.0 [4.2-11.6]; P < 0.001) as pseudoaldosteronism-related factors. Additionally, the daily Glycyrrhiza dose (OR = 2.1 [1.9-2.3]; P < 0.001) and duration of administration (>14 days, OR = 2.8 [1.7-4.5]; P < 0.001) were associated with adverse events. We did not observe an interaction between aging and hypertension. Careful follow-up is warranted during long-term Glycyrrhiza-containing Kampo formula use in patients with multiple clinical factors for pseudoaldosteronism.

Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

Exploration for the real causative agents of licorice-induced pseudoaldosteronism.

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 11ß-hydroxysteroid dehydrogenase (11ßHSD2) in tubular cells to cause pseudoaldosteronism. Since GA is not the substrates of these transporters, GA cannot inhibit 11ßHSD2 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-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate (2), and 18ß-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.

Risk Factors for Pseudoaldosteronism with Yokukansan Use: Analysis Using the Japanese Adverse Drug Report (JADER) Database.

Yokukansan is a Kampo formula that is commonly used by the elderly because it is expected to improve peripheral symptoms of dementia and delirium. However, side effects from its use are frequently reported in the elderly. In particular, pseudoaldosteronism caused by the licorice contained in yokukansan leads to hypertension, hypokalemia, and muscle weakness, which may result in death. This study aimed to identify the risk factors of pseudoaldosteronism with yokukansan use. Using cases reported in the Japanese Adverse Drug Report (JADER) database, the reporting odds ratio (ROR) was calculated and compared to assess the risk of pseudoaldosteronism for each licorice-containing Kampo formula. We also analyzed the risk factors for pseudoaldosteronism in patients taking yokukansan. Yokukansan (ROR 2.4, 95% confidence interval (CI) 1.9-2.8; p < 0.001) had a higher risk of pseudoaldosteronism than that of other licorice-containing Kampo formulas. Furthermore, the results of a logistic regression analysis in patients taking yokukansan showed that the licorice dose (OR 1.5, 95% CI 1.2-2.0; p < 0.01), older age (<70 years, OR 5.9, 95% CI 1.8-20; p < 0.01), dementia (OR 2.8, 95% CI 1.6-4.9; p < 0.001), low body weight (<50 kg, OR 2.2, 95% CI 1.1-3.5; p = 0.034) were risk factors for pseudoaldosteronism, Although not significant, treatment with loop diuretics (OR 1.8, 95% CI 0.98-3.5; p = 0.059) tended to increase the risk of pseudoaldosteronism. In summary, patients must understand the risk factors when considering taking yokukansan and reduce the licorice dose they consume.

A Study of Factors Associated with the Development of Pseudoaldosteronism in Outpatients.

Objective: The development of pseudoaldosteronism is shown to be mainly associated with four factors: daily dose of glycyrrhiza (licorice), duration of glycyrrhiza use, body size, and age. Recently, direct bilirubinemia and hypoalbuminemia are newly reported as possible factors that trigger pseudoaldosteronism due to glycyrrhiza ingestion. Pseudoaldosteronism occurs in the presence of combinations of these factors; therefore, the importance of each factor on the tolerance to glycyrrhiza loading is still unclear. Methods: In seven patients (63-78 years old, six women) who developed pseudoaldosteronism due to ingestion of glycyrrhiza-containing Kampo extract in their clinic, serum albumin and direct bilirubin (D-bil) levels were investigated. In six women, the authors evaluated the correlations between daily dose of glycyrrhiza ingested and each factor: age, height, weight, body mass index, body surface area (BSA), and duration of ingestion (Pearson's correlation coefficient). Results: No patients had abnormal levels of serum albumin or D-bil around the time of the onset. In six women, the highest correlation coefficient was observed between BSA and the glycyrrhiza dose in Kampo extract at the onset of pseudoaldosteronism. Conclusions: The findings suggested that in elderly women, BSA should be considered first as a factor for predicting the development of pseudoaldosteronism.

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

Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18ß-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM-1.8 µM) and 18ß-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM-4.2 µM). 3-Monoglucuronyl 18ß-glycyrrhetinic acid, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.

Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study.

Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin.

[Scientific Evaluation of Crude Drugs and Kampo Medicines Using the Eastern Blotting Method and Its Application to Biological Metabolic Studies].

　The scientific evaluation of crude drugs and kampo medicines (KMs) was demonstrated using the eastern blotting method with monoclonal antibodies (MAbs) against bioactive natural compounds. Scutellariae radix is one of the most important crude drugs used in KMs. Part of its pharmaceutical properties is due to the flavone glycoside baicalin (BI). A quantitative analysis method based on eastern blotting was developed for BI using an anti-BI MAb. A rapid, simple, sensitive, specific analytical system was subsequently established for BI with the eastern blotting technique using dot-blot and chemiluminescent methods. This system was useful as a high-throughput analytical method for the determination of BI in KMs as well as HPLC and enzyme-linked immunosorbent assay systems. Furthermore, an eastern blotting method was applied to the biological metabolic study of glycyrrhizic acid (GL), the major active constituent of licorice, for investigation of metabolites of GL such as 3-monoglucuronyl-glycyrrhetinic acid (3MGA) because licorice causes pseudoaldosteronism as a side effect. This approach may make it possible to determine the pathogenic agents of licorice-induced pseudoaldosteronism.

Diospyros rhodocalyx (Tako-Na), a Thai folk medicine, associated with hypokalemia and generalized muscle weakness: a case series.

INTRODUCTION: Diospyros rhodocalyx (Tako-Na) is a Thai folk medicine purported to promote longevity, treat impotence, etc. We present patients with hypokalemia, weakness and hypertension after consuming Tako-Na tea. CASE SERIES: Case 1: A 61-year-old man was brought in nine hours after drinking 400-500 mL of Tako-Na tea. One handful of Tako-Na bark was boiled in water to make tea. He had vomiting and watery diarrhea six hours after drinking it. He took no medications and had no history of hypertension. The only remarkable vital sign was BP 167/90 mmHg. Physical examination revealed generalized muscle weakness. Laboratory findings were potassium 2.7 mmol/L, bicarbonate 24 mmol/L, and transtubular potassium gradient (TTKG) 5.6. He was discharged the next day with a BP 140/90 mmHg and potassium 4.2 mmol/L. Case 2: A 78-year-old man, a friend of case 1, also drank Tako-Na tea from the same pot at the same time as case 1. He also had vomiting and diarrhea six hours later. He took no medications despite past history of hypertension (baseline SBP 140-160). Initial BP was 230/70 mmHg. He also had muscle weakness. Laboratory findings were potassium 3.3 mmol/L, bicarbonate 24 mmol/L, TTKG 7.37 and normal thyroid function. He was also discharged the next day with a BP 148/70 mmHg and potassium 4.2 mmol/L. Case 3-7: These were patients reported to a poison center and their potassium concentrations were 1.4, 1.4, 3.3, 1.3 and 1.2 mmol/L, respectively. Three of them were intubated and case 3 died. CONCLUSIONS: Tako-Na contains betulin, betulinic acid, taraxerone, lupeol, and lupenone. Their structures are similar to glycyrrhetic acid, the active metabolite of glycyrrhizic acid found in licorice which is well known to cause pseudoaldosteronism. Glycyrrhetic acid is potent in inhibiting 11-beta-hydroxysteroid dehydrogenase, and causes pseudoaldosteronism. We hypothesize that the compounds in Tako-Na act in the same way as glycyrrhetic acid in producing pseudoaldosteronism.

A semi-physiologically based pharmacokinetic pharmacodynamic model for glycyrrhizin-induced pseudoaldosteronism and prediction of the dose limit causing hypokalemia in a virtual elderly population.

Glycyrrhizin (GL) is a widely used food additive which can cause severe pseudoaldosteronism at high doses or after a long period of consumption. The aim of the present study was to develop a physiologically based pharmacokinetic (PBPK) pharmacodynamic (PD) model for GL-induced pseudoaldosteronism to improve the safe use of GL. Since the major metabolite of GL, glycyrrhetic acid (GA), is largely responsible for pseudoaldosteronism via inhibition of the kidney enzyme 11ß-hydroxysteroiddehydrogenase 2 (11ß-HSD 2), a semi-PBPK model was first developed in rat to predict the systemic pharmacokinetics of and the kidney exposure to GA. A human PBPK model was then developed using parameters either from the rat model or from in vitro studies in combination with essential scaling factors. Kidney exposure to GA was further linked to an Imax model in the 11ß-HSD 2 module of the PD model to predict the urinary excretion of cortisol and cortisone. Subsequently, activation of the mineralocorticoid receptor in the renin-angiotensin-aldosterone-electrolyte system was associated with an increased cortisol level. Experimental data for various scenarios were used to optimize and validate the model which was finally able to predict the plasma levels of angiotensin II, aldosterone, potassium and sodium. The Monte Carlo method was applied to predict the probability distribution of the individual dose limits of GL causing pseudoaldosteronism in the elderly according to the distribution of sensitivity factors using serum potassium as an indicator. The critical value of the dose limit was found to be 101 mg with a probability of 3.07%.

3-Monoglucuronyl glycyrrhretinic acid is a possible marker compound related to licorice-induced pseudoaldosteronism.

One of the most common adverse effects of traditional Japanese kampo and traditional Chinese medicine is pseudoaldosteronism caused by licorice. In this review, the authors describe the mechanisms of licorice-induced pseudoaldosteronism by the pharmacokinetics of chemical constituents and its metabolites containing licorice. Glycyrrhizin (GL), the main constituent of licorice, is absorbed as glycyrrhetinic acid (GA), which is a metabolite of GL produced by enterobacteria before its release into the circulation. Circulating GA is metabolized in the liver to become 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which is excreted into the bile via multidrug resistance protein 2 (Mrp2). If Mrp2 function is damaged for some reason, 3MGA is secreted from the liver into the circulation, and excreted into the urine via organic anion transporters expressed at the basolateral side of tubular epithelial cells. Circulating GA cannot be excreted into the urine since GA binds highly to serum albumin and thus does not pass through glomerular filtration and is not a substrate of transporters expressed on tubular epithelial cells. Licorice-induced pseudoaldosteronism develops due to the inhibition of type 2 11ß-hydrosteroid dehydrogenase (11ß-HSD2) which results in the accumulation of cortisol in tubular epithelial cells that activate mineral corticoid receptors to stimulate the excretion of potassium that results in hypokalemia. GA, unlike 3MGA, cannot pass through tubular epithelial cells and cannot inhibit the enzyme in the cells. Therefore, 3MGA may be a genuine causative agent for licorice-induced pseudoaldosteronism. When licorice is used, 3MGA in plasma or urine could function as a marker compound to prevent the adverse effects.

Risk factors for pseudoaldosteronism with rhabdomyolysis caused by consumption of drugs containing licorice and differences between incidence of these conditions in Japan and other countries: case report and literature review.

BACKGROUND: The pathogenesis of licorice-induced pseudoaldosteronism is thought to involve the inhibition of 11ß-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid. Some risk factors have been reported, but differences between Japan and other countries have not been reported. CASE PRESENTATION: A 79-year-old woman was hospitalized because of pseudoaldosteronism with rhabdomyolysis caused by ingestion of herbal medicines containing licorice. She had been prescribed shakuyakukanzobushito (decocted, 3 g of licorice) and keishikajutsubuto (decocted, 2 g of licorice) for the treatment of lower back pain and had been taking antihypertensive agents for the treatment of essential hypertension. After taking the herbal medicines for 2 weeks, the patient developed weakness of the extremities and pain in both thighs. On admission, she had hypertension, oliguria, an elevated serum creatine kinase level, hypokalemia, alkalemia associated with metabolic alkalosis, low plasma renin activity, and low plasma aldosterone levels. Intravenous and oral potassium supplementation and the administration of spironolactone resulted in the normalization of her condition within approximately 2 weeks. DISCUSSION: An analysis of case reports of pseudoaldosteronism with rhabdomyolysis revealed that in Japan, most cases occurred in elderly women with essential hypertension and were caused by drugs such as herbal medicines. In contrast, in other countries, many cases involved younger men, and the dominant causes were foods containing licorice. The use of herbal medicines is increasing all over the world, and when a patient with risk factors is prescribed an herbal medicine containing licorice, careful follow-up is required.

[Basic knowledge about Kampo for neurologists].

Kampo is a traditional form of medicine in Japan. The individual formulas of the Kampo medicines consist mainly of plant-derived crude drugs. Recently, extract products that maintain specific levels of quality have been commonly used for dosage formulation instead of decoction. Although severe side effects, including pseudoaldosteronism, interstitial pneumonitis, liver damage and mesenteric phlebosclerosis may occasionally arise in some patients, herbal formulations are generally safe compared with potent western medicines. Since the complicated interaction of a Kampo formulation is difficult to analyze pharmacologically, the use of each Kampo formula has been based on the empirical rules described in classical writings by clinicians. Currently, formula selection is not always based on the pathological recognition from the Oriental medicine perspective, because these ancient theories are not necessarily amenable to current clinical practice. Nevertheless, formula selection would be more appropriate, and the therapeutic efficacy would increase if the physicians understood the basic concepts of ki, ketsu, sui, yin-yang, hypofunction and hyperfunction, heat and cold, superficies and interior, the five parenchymatous viscera and the six stages of disease. Regardless of the primary diseases, many Kampo formulas are considered to be indicated for patients complaining of headache, dizziness and numbness, which are common symptoms in everyday practice in neurology.

Comparison of the exposure of glycyrrhizin and its metabolites and the pseudoaldosteronism after intravenous administration of alpha- and beta-glycyrrhizin in rat.

Glycyrrhizin, the major bioactive component in licorice root extract, exists as 2 isomers, α and ß-glycyrrhizin, and is associated with causing pseudoaldosteronism due to its principal metabolites, glycyrrhetinic acid and 3-monoglucuronyl-glycyrrhetinic acid. The aim of this study was to compare (a) the pharmacokinetics of glycyrrhizin and its metabolites in rat after the first and last intravenous doses of either α- or ß-glycyrrhizin administered once a day over 6 days, (b) kidney levels of the metabolites at 24 h after the last dose and (c) the urinary cortisol:cortisone ratio (as a biomarker of pseudoaldosteronism) in total urine collected for 24 h after the last dose.After the first dose, the clearance of glycyrrhizin in rats given α-isomer was significantly higher than in those given ß-isomer and the AUC0-24 h values of glycyrrhizin and the metabolites were all significantly higher in ß group than in α group. After the last dose, the AUC0-24 h values of glycyrrhizin and its metabolites were again significantly higher in rats given ß-isomer than those given α-isomer and were all higher than the corresponding values after the first dose. Moreover, only kidney levels of glycyrrhetinic acid were detected in ß group. The urinary cortisol:cortisone ratio was higher in rats given ß-isomer and the correlation coefficients of the ratios with the AUC0-24 h values of 2 metabolites were 0.81 and 0.89 respectively.The results of the present study indicate that α-glycyrrhizin is a safer drug than ß- glycyrrhizin probably due to a lower systemic exposure to the 2 metabolites.

3-Monoglucuronyl-glycyrrhretinic acid is a substrate of organic anion transporters expressed in tubular epithelial cells and plays important roles in licorice-induced pseudoaldosteronism by inhibiting 11ß-hydroxysteroid dehydrogenase 2.

Licorice (glycyrrhiza root) has been used as a herbal medicine worldwide with its main active constituent being glycyrrhizin (GL). Licorice sometimes causes adverse effects such as inducing pseudoaldosteronism by inhibiting type 2 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) caused by glycyrrhetinic acid (GA), a major metabolite of GL. In this study we compared the inhibitory effects of GA, GL, and 3-monoglucuronyl-glycyrrhetinic acid (3MGA), another metabolite of GL, on 11ß-HSD2 activity by using microsomes and rat kidney tissue slices. GA, 3MGA, and GL inhibited 11ß-HSD2 in rat kidney microsomes, with IC(50) values of 0.32, 0.26, and 2.2 µM, respectively. However, the inhibitory activity of these compounds was reduced markedly, in the slices, in a medium containing 5% bovine serum albumin. Assays using human embryonic kidney 293 cells with transient transformation in transporter genes showed that 3MGA is a substrate of human organic anion transporter (OAT) 1, human OAT3, and human organic anion-transporting peptide 4C1, whereas GA is not. When GA (100 mg/kg/day) was administered orally for 16 days to Eisai hyperbilirubinemic rats, plasma concentrations and urinary excretion of 3MGA were significantly higher, whereas the activity of 11ß-HSD2 in kidney microsomes was significantly lower compared with Sprague Dawley rats. These results suggest that 3MGA is actively transported into tubules through OATs, resulting in the inhibition of 11ß-HSD2. Because the plasma level of 3MGA depends on the function of hepatic transporters, monitoring 3MGA levels in plasma or urine may be useful for preventing pseudoaldosteronism when licorice or GL is prescribed to patients.

[Pseudoaldosteronism in an elderly man believed to be caused by the health food Shin-Gojoshin].

CASE: We report a 67-year-old man in whom pseudoaldosteronism developed following consumption of the health food Shin-Gojoshin. The patient began consuming Shin-Gojoshin in February 2007. His serum potassium level, which was within the normal range until he began consumption, gradually decreased to 3.0 mEq/L. The administration of potassium supplements and spironolactone was initiated. However, his hypokalemia persisted, and in December 2009, he was referred to our hospital for further examination. Laboratory data revealed hypokalemia, metabolic alkalosis, urinary potassium wasting, low plasma renin activity, and a low plasma aldosterone concentration. Pseudoaldosteronism was suspected and he was admitted. Although he reported no history of consumption of other traditional herbal medicines at the initial medical outpatient examination, he reported the consumption of Shin-Gojoshin in a medical interview taken on admission. Discontinuation of Shin-Gojoshin and potassium supplementation on admission successfully normalized his electrolyte imbalance. CONCLUSION: The present case describes the occurrence of pseudoaldosteronism induced by consumption of Shin-Gojoshin. A history of consumption of traditional herbal medicines and other health foods should be obtained, particularly in elderly individuals presenting with symptoms of pseudoaldosteronism.

[Hypertension and hypokalemia - a reninoma as the cause of suspected liquorice-induced arterial hypertension]. / Hypertonus und Hypokaliämie - Der Verdacht einer Lakritz-induzierten Hypertonie entpuppt sich als Reninom.

HISTORY AND CLINICAL FINDINGS: A 28-year-old woman presented with dizziness and arterial hypertension. She reported a daily intake of 300 mg liquorice. INVESTIGATIONS: Laboratory analysis revealed hypokalaemia of 2.5 mmol/l and an elevated serum renin activity of 18.6 µg/l/h. Abdominal ultrasound and magnetic resonance imaging showed a circumscribed non-homogenuous round lesion (18 × 22 mm) in the upper third of the right kidney. Selective catheterization of the renal veins revealed increased renin activity in blood from the right renal vein, suggestive of a renin-producing tumor. TREATMENT AND COURSE: Initially antihypertensive therapy with the direct renin receptor antagonist aliskiren was started and followed by a partial nephrectomy, which brought about adequate blood pressure and potassium levels. CONCLUSION: The constellation of hypokalaemia and hypertension often leads to important causes of secondary hypertension such as primary hyperaldosteronism or renal artery stenosis. But less frequent causes should also be considered in the differential diagnoses, such as liquorice overindulgence or reninoma.