Effect of honokiol on cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes

Abstract

Honokiol is a bioactive component isolated from the medicinal herbs Magnolia officinalis and Magnolia grandiflora that has antioxidative, anti-inflammatory, antithrombotic, and antitumor activities. The inhibitory potentials of honokiol on eight major human cytochrome P450 (CYP) enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, and four UDP-glucuronosyltransferases (UGTs) 1A1, 1A4, 1A9, and 2B7 in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. Honokiol strongly inhibited CYP1A2-mediated phenacetin O-deethylation, CYP2C8-mediated amodiaquine N-deethylation, CYP2C9-mediated diclofenac 4-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4-hydroxylation, and UGT1A9-mediated propofol glucuronidation with K(i) values of 1.2, 4.9, 0.54, 0.57, and 0.3 μM, respectively. Honokiol also moderately inhibited CYP2B6-mediated bupropion hydroxylation and CYP2D6-mediated bufuralol 1'-hydroxylation with K(i) values of 17.5 and 12.0 μM, respectively. These in vitro results indicate that honokiol has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and UGT1A9.

Figure 1

Chemical structure of honokiol.

Figure 2

Representative Dixon plots for the inhibitory effects of honokiol on (a) CYP1A2-catalyzed phenacetin O-deethylation, (b) CYP2B6-catalyzed bupropion hydroxylation, (c) CYP2C8-catalyd amodiaquine N-deethylation, (d) CYP2C9-catalyzed diclofenac 4-hydroxylation, (e) CYP2C19-catalyzed [S]-mephenytoin 4-hydroxylation, and (f) CYP2D6-catalyzed bufuralol 1'-hydroxylation in pooled human liver microsomes (H161). Each symbol represents the substrate concentration: (a) phenacetin 10 μM (∇), 20 μM (◯), 40 μM (∆), 80 μM (☐), (b) bupropion 10 μM (∇), 20 μM (◯), 40 μM (∆), 80 μM (☐), (c) amodiaquine, 1.0 μM (∇), 2.0 μM (◯), 4.0 μM (∆), 8.0 μM (☐); (d) diclofenac, 1.25 μM (∇), 2.5 μM (◯), 5 μM (∆), 10 μM (☐); (e) [S]-mephenytoin, 20 μM (∇), 40 μM (◯), 80 μM (∆), 160 μM (☐); (f) bufuralol, 1.0 μM (∇), 2.0 μM (◯), 4.0 μM (∆). Each data point represents the mean of triplicate experiments.

Figure 3

Representative Dixon plots for the inhibitory effects of honokiol on UGT1A9-catalyzed propofolglucuronidation in pooled human liver microsomes (H161). Each symbol represents the substrate concentration: propofol, 5 μM (∇), 10 μM (◯), 20 μM (∆), 40 μM (☐). Each data point represents the mean of triplicate experiments.