Exploration for the real causative agents of licorice-induced pseudoaldosteronism.
Exploration for the real causative agents of licorice-induced pseudoaldosteronism.
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甘草引起假性醛固酮增多症的真实的致病因素探讨。
DOI：
10.1007/s11418-021-01484-3
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发表时间：
2021-03
影响因子：
3.3
通讯作者：
Makino T
中科院分区：
文献类型：
--
作者：
Makino T
我调查了甘草引起的假性醛固酮增多症的病原体，这是日本传统汉方药物的常见副作用。甘草素（GL）是甘草的主要成分，经肠道细菌代谢后被吸收为甘草次酸（GA），再经肝脏代谢为3-单葡萄糖醛酸基甘草次酸（3 MGA）。在正常情况下，3 MGA通过多药耐药相关蛋白（Mrp）2排泄到胆汁中，因此，3 MGA不会出现在血液循环中。然而，在Mrp 2功能障碍的情况下，3 MGA出现在血液循环中，并通过有机阴离子转运蛋白（OAT）1和3通过肾小管分泌而不是肾小球过滤排泄到尿液中。此时，3 MGA抑制肾小管细胞中的2型11β-羟基类固醇脱氢酶（11β HSD 2），导致假性醛固酮增多症。由于GA不是这些转运蛋白的底物，因此GA不能抑制肾小管细胞中的11β HSD 2。因此，认为3 MGA是甘草诱导的假性醛固酮增多症的致病因子。之后，我从口服GA的Mrp 2缺陷大鼠的尿液中分离并鉴定了另外三种GL代谢产物，22 α-羟基-18 β-甘草次酸-3-O-硫酸酯-30-葡糖苷酸（1）、22α-羟基-18 β-甘草次酸-3-O-硫酸酯（2）和18β-甘草次酸-3-O-硫酸酯（3），结果表明，它们的血药浓度和尿药浓度均远高于3 MGA，药代动力学行为与3 MGA相似。在因甘草而发生横纹肌溶解的假性醛固酮增多症患者的血液中未检测到3 MGA，并且检测到高浓度的化合物3。此外，使用97名服用含甘草的汉方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名患者中，67名检测到血清中的GA（中值122 nM，5 nM-1.8 µM），68名检测到化合物3（中值239 nM，2 nM-4.2 µM），并且没有检测到GL、3 MGA、化合物1和2的情况。高血药浓度的化合物3与低血浆肾素活性、血浆醛固酮水平和血清钾水平相关。化合物3极有可能是假性醛固酮增多症的真正病原体。
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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影响因子：
4.6
作者：
Morinaga O;Ishiuchi K;Ohkita T;Tian C;Hirasawa A;Mitamura M;Maki Y;Yasujima T;Yuasa H;Makino T
通讯作者：
Makino T
影响因子：
--
作者：
EDWARDS, CRW
通讯作者：
EDWARDS, CRW
影响因子：
2.1
作者：
Jing, Jing;Ren, Weichao;Jing, Ning
通讯作者：
Jing, Ning
影响因子：
5.8
作者：
KATO, H;KANAOKA, M;KOBAYASHI, M
通讯作者：
KOBAYASHI, M
影响因子：
--
作者：
CONN, JW;ROVNER, DR;COHEN, EL
通讯作者：
COHEN, EL