Isolation of a novel glycyrrhizin metabolite as a causal candidate compound for pseudoaldosteronism.
Isolation of a novel glycyrrhizin metabolite as a causal candidate compound for pseudoaldosteronism.
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DOI：
10.1038/s41598-018-33834-9
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发表时间：
2018-10-22
影响因子：
4.6
通讯作者：
Makino T
中科院分区：
文献类型：
--
作者：
Morinaga O;Ishiuchi K;Ohkita T;Tian C;Hirasawa A;Mitamura M;Maki Y;Yasujima T;Yuasa H;Makino T
假性醛固酮增多症是与传统日本汉方药物相关的常见不良反应。其发病机制主要是由甘草中含有的甘草苷（GL）的代谢产物之一3-单葡萄糖醛酸基甘草次酸（3 MGA）引起的。我们研制了一种抗3 MGA单克隆抗体（MAb）和一种酶联免疫吸附试验（ELISA）系统，可以方便地检测患者血浆和尿液中的3 MGA。然而，我们发现GL的一些代谢产物与该单抗发生交叉反应。给Mrp 2缺陷型高胆红素血症大鼠（EHBRs）灌胃大黄酸（GA），在免疫印迹法阳性的指导下，从合并尿液中分离出GL的新代谢产物22α-羟基-18 β-大黄酸基-3-O-硫酸酯-30-葡萄糖醛酸苷（1）。1对2型11β-羟基类固醇脱氢酶（11β-HSD 2）的IC 50为2.0 µM。口服GA至EHBR后12 h，观察到1和GA的相似血浆浓度。化合物1通过尿液消除，而GA则不是。在用GA口服处理的Sprague-Dawley（SD）大鼠中，血浆和尿中都不存在化合物1。化合物1通过OAT 1和OAT 3主动转运到细胞中，而GA则不是。当在Mrp 2缺陷中产生时，化合物1代表假醛固酮增多症的潜在病原体，并且可以用作生物标志物以防止不良作用。
Pseudoaldosteronism is a common adverse effect associated with traditional Japanese Kampo medicines. The pathogenesis is mainly caused by 3-monoglucuronyl glycyrrhetinic acid (3MGA), one of the metabolites of glycyrrhizin (GL) contained in licorice. We developed an anti-3MGA monoclonal antibody (MAb) and an ELISA system to easily detect 3MGA in the plasma and urine of the patients. However, we found that some metabolites of GL cross-reacted with this MAb. Mrp2-deficient Eisai Hyperbilirubinemia rats (EHBRs) were administered glycyrrhetinic acid (GA), and we isolated 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1) from the pooled urine with the guidance of positive immunostaining of eastern blot as the new metabolite of GL. The IC50 of 1 for type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2) was 2.0 µM. Similar plasma concentrations of 1 and GA were observed 12 h after oral administration of GA to EHBR. Compound 1 was eliminated via urine, whereas GA was not. In Sprague–Dawley (SD) rats orally treated with GA, compound 1 was absent from both the plasma and the urine. Compound 1 was actively transported into cells via OAT1 and OAT3, whereas GA was not. Compound 1, when produced in Mrp2-deficiency, represents a potential causative agent of pseudoaldosteronism, and might be used as a biomarker to prevent the adverse effect.
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影响因子：
4.2
作者：
Morinaga, O;Nakajima, S;Shoyama, Y
通讯作者：
Shoyama, Y
影响因子：
5.8
作者：
KATO, H;KANAOKA, M;KOBAYASHI, M
通讯作者：
KOBAYASHI, M
影响因子：
5.8
作者：
AKAO, T;AOYAMA, M;KOBASHI, K
通讯作者：
KOBASHI, K
使用抗马兜铃酸 I 和 II 的单克隆抗体开发东部印迹技术，用于视觉检测马兜铃和细辛中的马兜铃酸
影响因子：
3.3
作者：
Li, Xiao-Wei;Morinaga, Osamu;Shoyama, Yukihiro
通讯作者：
Shoyama, Yukihiro
影响因子：
3.3
作者：
Morinaga, Osamu;Uto, Takuhiro;Shoyama, Yukihiro
通讯作者：
Shoyama, Yukihiro