Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A, Magnolin, and Yangambin Inhibit UDP-Glucuronosyltransferase 1A1 and 1A3 Activities in Human Liver Microsomes.

Hye Suk Lee,Im-Sook Song,Joo Young Lee,Yong-Yeon Cho,Han Chang Kang,Ria Park,Eun Jeong Park

doi:10.3390/pharmaceutics13020187

Hye Suk Lee, Im-Sook Song + Show 5 more

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https://doi.org/10.3390/pharmaceutics13020187

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Abstract

Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin are tetrahydrofurofuranoid lignans with various pharmacological activities found in Magnoliae Flos. The inhibition potencies of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin on six major human uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes were evaluated using liquid chromatography–tandem mass spectrometry and cocktail substrates. Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin inhibited UGT1A1 and UGT1A3 activities, but showed negligible inhibition of UGT1A4, UGT16, UGT1A9, and UGT2B7 activities at 200 μM in pooled human liver microsomes. Moreover, eudesmin, fargesin, epimagnolin A, magnolin, and yangambin noncompetitively inhibited UGT1A1-catalyzed SN38 glucuronidation with Ki values of 25.7, 25.3, 3.6, 26.0, and 17.1 μM, respectively, based on kinetic analysis of UGT1A1 inhibition in pooled human liver microsomes. Conversely, the aforementioned tetrahydrofurofuranoid lignans competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation with 39.8, 24.3, 15.1, 37.6, and 66.8 μM, respectively in pooled human liver microsomes. These in vitro results suggest the necessity of evaluating whether the five tetrahydrofurofuranoid lignans can cause drug–drug interactions with UGT1A1 and UGT1A3 substrates in vivo.

Highlights

Fargesin, epimagnolin A, magnolin, and yangambin (Figure 1) are the pharmacologically active tetrahydrofurofuranoid lignans found in Magnolia denudata
This study aimed to investigate the in vitro inhibitory potentials and inhibition kinetics of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin, that are major tetrahydrofurofuranoid lignans contained in NDC-052 and found in rat plasma samples [18], on UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 activities using pooled human liver microsomes to provide the underlying drug interaction potentials of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin
Yangambin jor tetrahydrofurofuranoid lignans that exist in the ethanol extract of flower bud of M

Summary

Introduction

Fargesin, epimagnolin A, magnolin, and yangambin (Figure 1) are the pharmacologically active tetrahydrofurofuranoid lignans found in Magnolia denudata. Desrousseaux, M. fargesii Cheng (family: Magnoliaceae), and Zanthoxylum armatum DC (family: Rutaceae) [1,2,3,4,5]. These lignans possess anti-inflammatory activity through the inhibitory effects on 5-lipoxygenase and nitric oxide synthase [5,6,7,8,9] and antitumor activity [10,11,12]. In addition to the anti-inflammatory and antitumor activity of tetrahydrofurofuranoid lignans, eudesmin showed bactericidal effect on Helicobacter pylori reference strain. Magnolin ameliorates contrast-induced nephropathy in rats via anti-oxidation and anti-apoptosis [17].

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