3-Monoglucuronyl Glycyrrhretinic Acid Is a Possible Marker Compound Related to Licorice-Induced Pseudoaldosteronism
3-Monoglucuronyl Glycyrrhretinic Acid Is a Possible Marker Compound Related to Licorice-Induced Pseudoaldosteronism
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DOI：
10.1248/bpb.b13-00997
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发表时间：
2014-06-01
影响因子：
2
通讯作者：
Makino, Toshiaki
中科院分区：
文献类型：
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作者：
Makino, Toshiaki
日本传统汉方和中药最常见的不良反应之一是甘草引起的假性醛固酮增多症。在这篇综述中，作者通过含甘草的化学成分及其代谢物的药代动力学描述了甘草诱导的假性醛固酮增多症的机制。甘草甜素 (GL) 是甘草的主要成分，以甘草次酸 (GA) 的形式被吸收，甘草次酸是肠细菌在释放到循环之前产生的 GL 的代谢产物。循环中的 GA 在肝脏中代谢成 3-单葡萄糖醛酸基甘草次酸 (3MGA)，通过多药耐药蛋白 2 (Mrp2) 排泄到胆汁中。如果Mrp2功能因某种原因受损，3MGA会从肝脏分泌到循环中，并通过肾小管上皮细胞基底外侧表达的有机阴离子转运蛋白排泄到尿液中。循环中的 GA 不能排泄到尿液中，因为 GA 与血清白蛋白高度结合，因此不能通过肾小球滤过，也不是肾小管上皮细胞上表达的转运蛋白的底物。甘草诱导的假性醛固酮增多症是由于抑制 2 型 11 β-氢类固醇脱氢酶 (11 β-HSD2) 导致皮质醇在肾小管上皮细胞中积聚，从而激活矿物皮质激素受体刺激钾的排泄，从而导致低钾血症。与3MGA不同，GA不能穿过肾小管上皮细胞，也不能抑制细胞内的酶。因此，3MGA 可能是甘草引起的假性醛固酮增多症的真正致病因子。使用甘草时，血浆或尿液中的 3MGA 可以作为标记化合物来防止不良反应。
One of the most common adverse effects of traditional Japanese kampo and traditional Chinese medicine is pseudoaldosteronism caused by licorice. In this review, the authors describe the mechanisms of licorice-induced pseudoaldosteronism by the pharmacokinetics of chemical constituents and its metabolites containing licorice. Glycyrrhizin (GL), the main constituent of licorice, is absorbed as glycyrrhetinic acid (GA), which is a metabolite of GL produced by enterobacteria before its release into the circulation. Circulating GA is metabolized in the liver to become 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which is excreted into the bile via multidrug resistance protein 2 (Mrp2). If Mrp2 function is damaged for some reason, 3MGA is secreted from the liver into the circulation, and excreted into the urine via organic anion transporters expressed at the basolateral side of tubular epithelial cells. Circulating GA cannot be excreted into the urine since GA binds highly to serum albumin and thus does not pass through glomerular filtration and is not a substrate of transporters expressed on tubular epithelial cells. Licorice-induced pseudoaldosteronism develops due to the inhibition of type 2 11 beta-hydrosteroid dehydrogenase (11 beta-HSD2) which results in the accumulation of cortisol in tubular epithelial cells that activate mineral corticoid receptors to stimulate the excretion of potassium that results in hypokalemia. GA, unlike 3MGA, cannot pass through tubular epithelial cells and cannot inhibit the enzyme in the cells. Therefore, 3MGA may be a genuine causative agent for licorice-induced pseudoaldosteronism. When licorice is used, 3MGA in plasma or urine could function as a marker compound to prevent the adverse effects.