Abstract
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 (P < 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 IC50 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.
Footnotes
- Received October 7, 2021.
- Accepted February 11, 2022.
This work was supported by the National Natural Science Funds of China [Grants 82074109, 81873078, 81374051, and 81773687]; the Science and Research Program of Shanghai Municipal Health Commission [Grant 201740094]; the Science and Research Program of Traditional Chinese Medicine of Shanghai Municipal Health Commission [Grant 2018YP001]; and MHHFDU-SPFDU Joint Research Fund [Grants RO-MY201707 and 2021MHJC11].
↵1 X.Y. and G.Z. contributed equally to this work.
↵
This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
Log in using your username and password
Purchase access
Inhibition of hUGT1A1-Mediated Bilirubin Glucuronidation by Flavonoids
