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.

我调查了甘草引起的假醛固酮增多症的病因，这是日本传统汉方药物的常见副作用。甘草的主要成分甘草甜素（GL）在被肠道细菌代谢为甘草次酸（GA）之后被吸收，然后在肝脏中代谢为3-单葡糖醛酸-甘草次酸（3MGA）。在正常情况下，3MGA通过多药耐药相关蛋白（Mrp）2排泄到胆汁中，因此3MGA不会出现在血液循环中。然而，蛋白2的功能障碍下，3MGA出现在血液循环和通过经由有机阴离子转运体（OAT）1和3不肾小球滤过但肾小管分泌排入尿此时，3MGA抑制2型11 β羟基类固醇脱氢酶（11βHSD2）在肾小管细胞中引起假醛固酮增多症。由于GA不是这些转运蛋白的底物，GA不能抑制11 β在肾小管细胞HSD2。因此，认为3MGA是甘草诱导的假醛固酮增多症的病原体。在那之后，我分离并鉴定其他三个GL代谢产物，22 α -羟基- 18 β -glycyrrhetyl -3- ö -sulfate-30-葡糖苷酸（1），22 α -羟基- 18 β -glycyrrhetyl -3- ö -sulfate （2），和18 β -glycyrrhetyl -3- ö -sulfate（3）于口服GA的Mrp2缺陷大鼠的尿液中），发现它们的血液和尿液浓度远高于3MGA，并且其药代动力学行为与3MGA相似。在由于甘草引起横纹肌溶解的假醛固酮增多症患者的血液中未检测到3MGA，并且以高浓度检测到化合物3。此外，还对97名服用甘草甘榜药物的患者的血清和尿液进行了多中心回顾性研究。在总共97位患者中，有67位检测到血清中的GA（中位值为122 nM，5 nM–1.8 µM），有68位检测到化合物3（中位值为239 nM，2 nM–4.2 µM），没有检测到GL ，3MGA，化合物1和2。化合物3的血药浓度高与血浆肾素活性低，血浆醛固酮水平和血清钾水平有关。化合物3是假性醛固酮增多症的真正病因很可能。