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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BackgroundThere have been a few but not precise surveys of the current status of traditional Japanese Kampo education at medical schools in Japan. Our aim was to identify problems and suggest solutions for a standardized Kampo educational model for all medical schools throughout Japan.MethodsWe surveyed all 80 medical schools in Japan regarding eight items related to teaching or studying Kampo medicine: (1) the number of class meetings, target school year(s), and type of classes; (2) presence or absence of full-time instructors; (3) curricula contents; (4) textbooks in use; (5) desire for standardized textbooks; (6) faculty development programmes; (7) course contents; and (8) problems to be solved to promote Kampo education. We conducted descriptive analyses without statistics.ResultsEighty questionnaires were collected (100%). (1) There were 0 to 25 Kampo class meetings during the 6 years of medical school. At least one Kampo class was conducted at 98% of the schools, ≥4 at 84%, ≥8 at 44%, and ≥16 at 5%. Distribution of classes was 19% and 57% for third- and fourth-year students, respectively. (2) Only 29% of schools employed full-time Kampo medicine instructors. (3) Medicine was taught on the basis of traditional Japanese Kampo medicine by 81% of the schools, Chinese medicine by 19%, and Western medicine by 20%. (4) Textbooks were used by 24%. (5) Seventy-four percent considered using standardized textbooks. (6) Thirty-three percent provided faculty development programmes. (7) Regarding course contents, “characteristics” was selected by 94%, “basic concepts” by 84%, and evidence-based medicine by 64%. (8) Among the problems to be solved promptly, curriculum standardization was selected by 63%, preparation of simple textbooks by 51%, and fostering instructors responsible for Kampo education by 65%.ConclusionsJapanese medical schools only offer students a short time to study Kampo medicine, and the impetus to include Kampo medicine in their curricula varies among schools. Future Kampo education at medical schools requires solving several problems, including curriculum standardization.