Isolation of a novel glycyrrhizin metabolite as a causal candidate compound for pseudoaldosteronism

Morinaga, Osamu; Ishiuchi, Kan’ichiro; Ohkita, Takeshi; Tian, Chuanting; Hirasawa, Asuka; Mitamura, Miaki; Maki, Yasuhito; Yasujima, Tomoya; Yuasa, Hiroaki; Makino, Toshiaki

doi:10.1038/s41598-018-33834-9

Cited by 28 publications

(44 citation statements)

References 27 publications

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“…In terms of safety, we found that OCG capsules showed a satisfactory safety profile for patients with chronic eczema, as no patients experienced serious adverse events during our study. Nevertheless, long-term use of OCG may increase the risk of some adverse events, such as pseudoaldosteronism [25,26]. Known effects of pseudoaldosteronism were observed in our study, as three (3.2%) patients developed lower extremity edema, one (1.1%) experienced hypokalemia, and two (2.1%) had new-onset high blood pressure.…”

Section: Discussionsupporting

confidence: 49%

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

Mei

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Background. Glycyrrhizin is widely used in skin disorders, such as psoriasis, alopecia areata, and allergic diseases, but has not been extensively studied in patients with chronic eczema. Objective. To evaluate the efficacy and safety of oral compound glycyrrhizin (OCG) plus topical corticosteroid (TCS) in adults with chronic eczema. Methods. This was a multicenter, randomized, double-blind, placebo-controlled study in patients with chronic eczema (n = 199). Randomized participants from 6 centers in China received either 75 mg OCG capsules or placebo capsules three times a day and TCS (i.e., 0.1% mometasone furoate ointment) once a day for 28 days. Efficacy was determined by analyzing the mean change from the baseline using standardized measures including the Investigator’s Global Assessment (IGA) score, Eczema Area and Severity Index (EASI), and the visual analogue scale score (VAS) of itching. Results. Decreases in absolute EASI were significantly greater in the OCG-treated group versus placebo on day 14 (−3.41 ± 1.41 vs. −2.71 ± 1.25, P<0.001) and day 28 (−7.39 ± 1.71 vs. −6.64 ± 1.75, P=0.003). OCG-treated patients also saw greater benefit in other EASI metrics including EASI-50 (96.8% vs. 87.9%, P=0.021) and EASI-75 (47.9% vs. 21.2%, P<0.001) on day 28 compared with placebo. The absolute IGA score reductions were also significantly greater in the OCG group than the placebo (all P<0.05). In addition, proportions of patients who achieve clear (0) IGA scores or almost clear (1) IGA scores were significantly higher in the treated group than placebo on day 14 (22.8% vs. 6.2%, P=0.001) and day 28 (93.5% vs. 79.4%, P=0.005). Moreover, the proportions of patients with reduced pruritus were significantly greater in the treated group than placebo on day 28 (94.7% vs. 83.8%, P=0.016) and eczema recurrence was notably less in the OCG group versus placebo (3.19% vs. 12.12%, P=0.021). Eleven patients experienced adverse events, but there was no significant difference in the proportion of patients affected (3.0% vs. 8.5%, P>0.05). The most common adverse events were edema of both lower limbs. Conclusion. For adults with chronic eczema, OCG capsules combined with TCS is an effective and well-tolerated treatment, suggesting that OCG may be a useful nonsteroidal agent with an additional effect for the treatment of chronic eczema by TCS.

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Section: Discussionsupporting

confidence: 49%

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

Mei

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…We found that most of 2 and 3 in plasma was bound to albumin, suggesting that these two compounds would not be eliminated into the urine via glomerular filtration, but rather via tubular secretion. As 1 had a high binding ratio to albumin and was a substrate for OAT1 and 3 18 and 2 and 3 share a high binding ratio to albumin, these compounds can be transported into the cells actively via OAT1 and 3, and eliminated into the urine by tubular secretion. As GA also has a high binding ratio to albumin but is not a substrate for OATs, GA was not detected in the urine in either SD rats or EHBRs.…”

Section: Discussionmentioning

confidence: 99%

“…From these results, we developed an anti-3MGA-monoclonal antibody (mAb) and an enzyme-linked immunosorbent assay (ELISA) to easily detect 3MGA in the blood or urine of patients who took licorice, in order to prevent pseudoaldosteronism by predicting the individual body constitution causing this condition without using expensive instruments such as LC-MS/MS 18 . However, 3MGA detected by ELISA in the plasma and urine of EHBRs treated with GA was observed at concentrations much higher than those analyzed using LC-MS/MS, suggesting that the anti-3MGA-mAb cross-reacted with other metabolites of GA 18 . Eastern blot analysis using anti-3MGA-mAb with the urine from EHBRs treated with GA revealed another metabolite, 22 α -hydroxy-18 β -glycyrrhetyl-3- O -sulfate-30-glucuronide ( 1 , Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Eastern blot analysis using anti-3MGA-mAb with the urine from EHBRs treated with GA revealed another metabolite, 22 α -hydroxy-18 β -glycyrrhetyl-3- O -sulfate-30-glucuronide ( 1 , Fig. 1A) as a new natural product 18 . Although the inhibitory titer of 1 on 11 β -HSD2 was lower than that of 3MGA, its plasma concentration in EHBRs treated with GA was higher, making it a candidate for the causative agent of licorice-induced pseudoaldosteronism 18 .…”

Section: Introductionmentioning

confidence: 99%

“…1A) as a new natural product 18 . Although the inhibitory titer of 1 on 11 β -HSD2 was lower than that of 3MGA, its plasma concentration in EHBRs treated with GA was higher, making it a candidate for the causative agent of licorice-induced pseudoaldosteronism 18 .…”

Section: Introductionmentioning

confidence: 99%

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18β-glycyrrhetyl-3-O-sulfate would be a causative agent of licorice-induced pseudoaldosteronism

Ishiuchi

Morinaga

Ohkita

et al. 2019

Sci Rep

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Licorice-induced pseudoaldosteronism is a common adverse effect in traditional Japanese Kampo medicine, and 3-monoglucuronyl glycyrrhetinic acid (3MGA) was considered as a causative agent of it. Previously, we found 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), one of the metabolites of glycyrrhizin (GL) in the urine of Eisai hyperbilirubinuria rats (EHBRs) treated with glycyrrhetinic acid (GA), and suggested that it is also a possible causative agent of pseudoaldosteronism. The discovery of 1 also suggested that there might be other metabolites of GA as causal candidates. In this study, we found 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate (2) and 18β-glycyrrhetyl-3-O-sulfate (3) in EHBRs’ urine. 2 and 3 more strongly inhibited rat type 2 11β-hydroxysteroid dehydrogenase than 1 did in vitro. When EHBRs were orally treated with GA, GA and 1–3 in plasma and 1–3 in urine were detected; the levels of 3MGA were quite low. 2 and 3 were shown to be the substrates of organic anion transporter (OAT) 1 and OAT3. In the plasma of a patient suffering from pseudoaldosteronism with rhabdomyolysis due to licorice, we found 8.6 µM of 3, 1.3 µM of GA, and 87 nM of 2, but 1, GL, and 3MGA were not detected. These findings suggest that 18β-glycyrrhetyl-3-O-sulfate (3) is an alternative causative agent of pseudoaldosteronism, rather than 3MGA and 1.

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The Yin and Yang of traditional Chinese and Western medicine

et al. 2021

Medicinal Research Reviews

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The success of Western Scientific approaches to medicine, over the last 150 years, can be measured by substantial increases in life expectancy, reductions in infant mortality and the virtual elimination of many infectious diseases accompanied by development of effective management practices for noncommunicable diseases. However, major challenges remain in the form of infectious diseases that evolve resistance to pharmaceuticals rapidly, new diseases, particularly those caused by viruses and effective longterm treatments for chronic, noncommunicable diseases. Traditional Chinese Medicine (TCM) can offer complementary treatments based on personalised interventions, informed by knowledge accumulated from empirical observations gathered over centuries of practice, that address the impact of disease on the whole body. We provide examples of both infectious and noncommunicable diseases where the combination of Western Scientific Medicine (WSM) and TCM can benefit patients in terms of the speed and efficacy of recovery or disease management. TCM is a healing skill based on practice, while WSM is scientific, based on experiments. Against this background, an understanding of the mechanisms of action This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Isolation of a novel glycyrrhizin metabolite as a causal candidate compound for pseudoaldosteronism

Cited by 28 publications

References 27 publications

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study of Compound Glycyrrhizin Capsules Combined with a Topical Corticosteroid in Adults with Chronic Eczema

18β-glycyrrhetyl-3-O-sulfate would be a causative agent of licorice-induced pseudoaldosteronism

The Yin and Yang of traditional Chinese and Western medicine

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