Yang Xiaolei, Zhu Guanghao, Zhang Ying, Wu Xubo, Liu Bei, Liu Ye, Yang Qing, Du Wandi, Liang Jingru, Hu Jiarong, Yang Ping, Ge Guangbo, Cai Weimin, Ma Guo
School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.).
School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
Drug Metab Dispos. 2022 May;50(5):552-565. doi: 10.1124/dmd.121.000714. Epub 2022 Mar 3.
Bilirubin-related adverse drug reactions (ADRs) or malady (e.g., jaundice) induced by some herbs rich in certain flavonoids have been widely reported. However, the causes and mechanisms of the ADRs are not well understood. The aim of this paper was to explore the mechanism of Shuang-huang-lian (SHL) injections and its major constituents-induced jaundice via inhibiting human UDP-glucuronosyltransferases1A1 (hUGT1A1)-mediated bilirubin glucuronidation. The inhibitory effects of SHL and its major constituents in the herbal medicine, including baicalein (BAI), baicalin (BA), and hyperoside (HYP), on bilirubin glucuroBBREVInidation were investigated. This study indicated that the average formation rates of bilirubin glucuronides [i.e., mono-glucuronide 1 (BMG1), BMG2, and bilirubin diglucuronide] displayed significant differences < 0.05). Specifically, the formation of BMGs was favored regardless of whether an inhibitor was absent or present. SHL, BAI, BA, and HYP dose-dependently inhibit bilirubin glucuronidation, showing the IC values against total bilirubin glucuronidation were in the range of (7.69 ± 0.94)-(37.09 ± 2.03) μg/ml, (4.51 ± 0.27)-(20.84 ± 1.99) μM, (22.36 ± 5.74)-(41.35 ± 2.40) μM, and (15.16 ± 1.12)-(42.80 ± 2.63) μM for SHL, BAI, BA, and HYP, respectively. Both inhibition kinetics assays and molecular docking simulations suggested that SHL, BAI, BA, and HYP significantly inhibited hUGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibition. Collectively, some naturally occurring flavonoids (BAI, BA, and HYP) in SHL have been identified as the inhibitors against hUGT1A1-mediated bilirubin glucuronidation, which well explains the bilirubin-related ADRs or malady triggered by SHL in clinical settings. SIGNIFICANCE STATEMENT: Herbal products and their components (e.g., flavonoids), which been widely used across the entire world, may cause liver injury. As a commonly used herbal products rich in flavonoids, SHL injections easily lead to symptoms of liver injury (e.g., jaundice) owing to significant inhibition of hUGT1A1-mediated bilirubin glucuronidation by its flavonoid components (i.e., baicalein, baicalin, and hyperoside). Herb-induced bilirubin-related ADRs and the associated clinical significance should be seriously considered.
一些富含特定黄酮类化合物的草药引起的与胆红素相关的药物不良反应（ADR）或病症（如黄疸）已被广泛报道。然而，这些ADR的原因和机制尚未完全明确。本文旨在探讨双黄连（SHL）注射液及其主要成分通过抑制人尿苷二磷酸葡萄糖醛酸转移酶1A1（hUGT1A1）介导的胆红素葡萄糖醛酸化诱导黄疸的机制。研究了SHL及其草药中的主要成分，包括黄芩素（BAI）、黄芩苷（BA）和金丝桃苷（HYP）对胆红素葡萄糖醛酸化的抑制作用。本研究表明，胆红素葡萄糖醛酸酯（即单葡萄糖醛酸酯1（BMG1）、BMG2和胆红素二葡萄糖醛酸酯）的平均形成率显示出显著差异（<0.05）。具体而言，无论是否存在抑制剂，BMG的形成均占优势。SHL、BAI、BA和HYP均呈剂量依赖性抑制胆红素葡萄糖醛酸化，其对总胆红素葡萄糖醛酸化的IC值范围分别为（7.69±0.94）-（37.09±2.03）μg/ml、（4.51±0.27）-（20.84±1.99）μM、（22.36±5.74）-（41.35±2.40）μM和（15.16±1.12）-（42.80±2.63）μM。抑制动力学分析和分子对接模拟均表明，SHL、BAI、BA和HYP通过混合型抑制显著抑制hUGT1A1介导的胆红素葡萄糖醛酸化。总体而言，SHL中一些天然存在的黄酮类化合物（BAI、BA和HYP）已被确定为hUGT1A1介导的胆红素葡萄糖醛酸化的抑制剂，这很好地解释了SHL在临床环境中引发的与胆红素相关的ADR或病症。重要声明：在全球广泛使用的草药产品及其成分（如黄酮类化合物）可能会导致肝损伤。作为一种常用的富含黄酮类化合物的草药产品，SHL注射液因其黄酮类成分（即黄芩素、黄芩苷和金丝桃苷）对hUGT1A1介导的胆红素葡萄糖醛酸化的显著抑制作用，容易导致肝损伤症状（如黄疸）。应认真考虑草药引起的与胆红素相关的ADR及其相关的临床意义。
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