18β-glycyrrhetyl-3-O-sulfate would be a causative agent of licorice-induced pseudoaldosteronism
18β-glycyrrhetyl-3-O-sulfate would be a causative agent of licorice-induced pseudoaldosteronism
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DOI：
10.1038/s41598-018-38182-2
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发表时间：
2019-02-07
影响因子：
4.6
通讯作者：
Makino, Toshiaki
中科院分区：
文献类型：
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作者：
Ishiuchi, Kan'ichiro;Morinaga, Osamu;Makino, Toshiaki
甘草引起的假性醛固酮增多症是日本传统汉方药物中常见的不良反应，3-单葡萄糖醛酸基大黄酸（3 MGA）被认为是其致病因子。此前，我们发现22 α-羟基-18 β-大黄酸基-3-O-硫酸酯-30-葡萄糖醛酸苷（1），大黄次酸（GA）处理的高胆红素尿大鼠（EHBRs）尿中的甘草甜素（GL）的代谢物之一，并提示它也可能是假性醛固酮增多症的一个致病因子。1的发现还表明可能存在GA的其他代谢产物作为因果候选物。在本研究中，我们在EHBRs的尿液中发现了22 α-羟基-18 β-大黄酸-3-O-硫酸酯（2）和18 β-大黄酸-3-O-硫酸酯（3）。2和3更强烈地抑制大鼠2型11 β-羟基类固醇脱氢酶比1在体外。用GA治疗EHBRs时，血浆中可检出GA和1-3，尿中可检出1 -3，而3 MGA含量很低。2和3被证明是有机阴离子转运蛋白（OAT）1和OAT 3的底物。在一位患有假性醛固酮增多症并伴有甘草所致横纹肌溶解症的患者的血浆中，我们发现8.6 μ M的3、1.3 μ M的GA和87 nM的2，但未检测到1、GL和3 MGA。这些发现表明，18 β-大黄酸-3-O-硫酸酯（3）是假性醛固酮增多症的替代致病因子，而不是3 MGA和1。
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 22a-hydroxy-18 beta-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 22a-hydroxy-18-beta-glycyrrhetyl-3-O-sulfate (2) and 18 beta-glycyrrhetyl-3-O-sulfate (3) in EHBRs' urine. 2 and 3 more strongly inhibited rat type 2 11 beta-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 mu M of 3, 1.3 mu M of GA, and 87 nM of 2, but 1, GL, and 3MGA were not detected. These findings suggest that 18 beta-glycyrrhetyl-3-O-sulfate (3) is an alternative causative agent of pseudoaldosteronism, rather than 3MGA and 1.