Abstract
The adverse effects of Polygonum (P.) multiflorum, including abnormal bilirubin metabolism, are a serious public health issue. As uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) is the only enzyme responsible for bilirubin metabolism, we investigated the inhibitory effect of a P. multiflorum extract and 10 anthraquinone and dianthrone compounds on UGT1A1 in rat liver microsomes in vitro. The P. multiflorum extract exhibited the strongest inhibitory effect on UGT1A1 activity (inhibition constant [Ki] = 0.3257 μM, 1422 μg of material/mL), followed by cis-emodin dianthrones (Ki = 0.8630 μM), trans-emodin dianthrones (Ki = 1.083 μM), emodin-8-O-glc (Ki = 3.425 μM), and polygonumnolide C2 (Ki = 4.291 μM). Analysis of the structure–activity relationships of these compounds suggested that the spatial orientation of the molecules and the presence of particular functional groups affect UGT1A1 inhibition. A mechanistic analysis showed that all the tested compounds docked into two of the nine active sites of UGT1A1 and suggested that hydrophobic interactions and hydrogen bonds are important for the affinity of the tested compounds for UGT1A1; moreover, their interaction energies were generally in agreement with the Ki values. These findings provide insight into adverse reactions to P. multiflorum and identify the pharmacophores involved in inhibition of UGT1A1.
Highlights
P. multiflorum is among the most frequently used medicinal plants in China
We hypothesized that the abnormal bilirubin metabolism and hyperbilirubinemia observed following administration of P. multiflorum could be a result of UGT1A1 inhibition, primarily by quinones
Different concentrations of an ethanol P. multiflorum extract and its 10 major components were screened for their inhibition of
Summary
P. multiflorum (common names: Polygonum multiflorum Thunb[1], Polygoni Multiflora Radix[2], Fallopia multiflora, Heshouwu[3], fleeceflower root[4,5], Polygoni multiflori[6], and foti root7) is among the most frequently used medicinal plants in China. Because the structures of rhein and physcion are similar to that of emodin, whereas their activity and mode of inhibition differ markedly, the former two compounds may bind to other sites of UGT1A1. The two π systems and multiple hydroxyl groups of these two compounds may increase their affinity for UGT1A1 by facilitating hydrophobic interactions and hydrogen bonding.
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