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 injections (SHL) 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 glucuronidation were investigated. This study indicated that the average formation rates of bilirubin glucuronides (i.e., BMG1, BMG2, BDG) displayed significant differences (P <0.05), specially, the formation of mono-glucuronides (BMGs) was favored regardless whether an inhibitor was absent or presence. SHL, BAI, BA and HYP dose-dependently inhibit bilirubin glucuronidation, showing the IC50 values against total bilirubin glucuronidation (TBG) were in the range of (7.69 {plus minus} 0.94) μg/mL - (37.09 {plus minus} 2.03) μg/mL, (4.51 {plus minus} 0.27) μM - (20.84 {plus minus} 1.99) μM, (22.36 {plus minus} 5.74) μM - (41.35 {plus minus} 2.40) μM, and (15.16 {plus minus} 1.12) μM - (42.80 {plus minus} 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 in the whole world, may cause liver injury. As a commonly used herbal products rich in flavonoids, Shuang-huang-lian injections (SHL), 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, hyperoside). Herbs-induced bilirubin-related ADRs and its associated clinical significance should be seriously considered.
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