甘草[主要成分,甘草酸(GL)]广泛用作食品甜味剂和草药。偶尔,甘草消费导致假醛醛固酮增多症作为导致水肿的副作用,低钾血症,和由于矿物质皮质激素受体过度活跃引起的高血压。我们旨在检测人体血液和尿液样本中的GL代谢物,并确定GL代谢物与假醛固酮增多症之间的病理关系。对于这个多中心,回顾性,横断面研究,我们招募了去过庆应大学医院康波医学中心的患者,千叶大学医院日本东方(康波)医学系,金泽大学医院日本东方(Kampo)医学诊所,以及2011年11月至2018年7月在Kameda医学中心的东方医学系。我们收集了实验室数据,包括血清钾浓度,肾素和醛固酮的血浆活性,以及在服用含甘草的草药制剂时出现过假性醛固酮增多症症状/体征的参与者的残余血液和/或尿液样本,并使用高选择性液相色谱串联质谱仪系统测量GL代谢物。我们登记了97名参与者(平均年龄60±15岁;男性:女性14:83)。在67份血清样品中检测到18β-甘草次酸(GA)(中位数122nM,在68个样品中的范围为5nM-1.8µM)和18β-甘草次基-3-O-硫酸盐(化合物3)(中位数239nM,范围2nM-4.2µM)。3-单葡糖醛酸基18β-甘草次酸,22α-羟基-18β-甘草基-3-O-硫酸-30-葡糖苷酸,22α-羟基-18β-甘草基-3-O-硫酸盐,和GL本身没有或很少被检测到。我们没有发现血压或外周水肿与血清GL代谢物浓度之间的任何相关性。磺基转移酶2A1催化GA向化合物3的代谢反应,化合物3是人血液中的主要GL代谢物。高血清浓度的化合物3与低肾素有关,醛固酮,和钾水平,提示化合物3与甘草诱导的假醛固酮增多症之间的病理关系。这是第一项确定新代谢物之间关联的研究,化合物3和假醛固酮增多症的发生率,强调它是一个有前途的生物标志物。
Liquorice [main ingredient,
glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional
study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18β-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM-1.8 µM) and 18β-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM-4.2 µM). 3-Monoglucuronyl 18β-glycyrrhetinic acid, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first
study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.