Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5'-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes.

Soon-Sang Kwon,Ju-Hyun Kim,Yong Cho,Hye Lee,Sei-Ryang Oh,Hyeon-Uk Jeong

doi:10.3390/molecules21050554

Abstract

Aschantin is a bioactive neolignan found in Magnolia flos with antiplasmodial, Ca2+-antagonistic, platelet activating factor-antagonistic, and chemopreventive activities. We investigated its inhibitory effects on the activities of eight major human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes of human liver microsomes to determine if mechanistic aschantin–enzyme interactions were evident. Aschantin potently inhibited CYP2C8-mediated amodiaquine N-de-ethylation, CYP2C9-mediated diclofenac 4′-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4′-hydroxylation, and CYP3A4-mediated midazolam 1′-hydroxylation, with Ki values of 10.2, 3.7, 5.8, and 12.6 µM, respectively. Aschantin at 100 µM negligibly inhibited CYP1A2-mediated phenacetin O-de-ethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated bupropion hydroxylation, and CYP2D6-mediated bufuralol 1′-hydroxylation. At 200 µM, it weakly inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A6-catalyzed N-acetylserotonin glucuronidation, and UGT1A9-catalyzed mycophenolic acid glucuronidation, with IC50 values of 131.7, 144.1, and 71.0 µM, respectively, but did not show inhibition against UGT1A3, UGT1A4, or UGT2B7 up to 200 µM. These in vitro results indicate that aschantin should be examined in terms of potential interactions with pharmacokinetic drugs in vivo. It exhibited potent mechanism-based inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4.

Highlights

IntroductionAschantin (Figure 1) is a bioactive neolignan found in Magnolia flos and Hernandia nymphaeifolia [1]
Our in vitro results suggest that aschantin should be examined in terms of potential in vivo pharmacokinetic drug interactions caused by inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4
The degrees of inhibition of aschantin toward CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were evaluated using pooled human liver microsomes employing a cocktail of cytochrome P450 (CYP) substrates and liquid chromatography-tandem mass spectrometry (LC-MS/MS)

Summary

Introduction

Aschantin (Figure 1) is a bioactive neolignan found in Magnolia flos and Hernandia nymphaeifolia [1]. St. John’s wort arewith associated withinteractions herb–drug attributable to inhibition to and/or induction of drug-metabolizing enzymes [14,15,16,17]. Lignans interactions attributable inhibition and/or induction of drug-metabolizing enzymes including honokiol [18], machilin. B [22], phyllantin, hypophyllantin and podophyllotoxin cause herb–drug interactions inhibition of CYP enzymes. In this thisstudy, study,we we evaluated inhibitory effects of aschantin onactivities the activities of major eight enzymes. Evaluated thethe inhibitory effects of aschantin on the of eight major human enzymes

Discussion were evaluated in

Materials and Reagents

Inhibitory Effects of Aschantin on CYP2B6 in Human Liver Microsomes

Mechanism-Based Inhibition of CYP Activities by Aschantin

Data analysis

Conclusions