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 Ki 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 Ki 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.
Highlights
IntroductionKnown as (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol, Figure 1), is a biologically active component with antioxidative [1,2,3], anti-inflammatory [4,5,6,7,8], antithrombotic [9], neuroprotective [10,11], antinociceptive [12,13], antidepressant-like [14], and antitumor [15,16,17,18,19,20,21]
The inhibitory potencies of honokiol were not significantly affected after a 30 min preincubation with human liver microsomes in the presence of NADPH (Table 1), indicating that honokiol does not inhibit cytochrome P450 (CYP) in a time-dependent manner
The effect of honokiol on eight CYPs and four UGTs was determined across a wide range of substrates and honokiol concentrations using human liver microsomes
Summary
Known as (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol, Figure 1), is a biologically active component with antioxidative [1,2,3], anti-inflammatory [4,5,6,7,8], antithrombotic [9], neuroprotective [10,11], antinociceptive [12,13], antidepressant-like [14], and antitumor [15,16,17,18,19,20,21]. The underlying mechanisms of herb-drug interactions typically involve inhibition or induction of cytochrome P450 (CYP) enzymes, UDP-glucuronosyltransferase (UGT) enzymes, and drug transporters [25,26,27,28,29]. Bergamotin, a major furanocoumarin found in grapefruit juice, has been reported to increase the blood concentration of drugs by inhibiting hepatic CYP3A activity, thereby enhancing the toxicity of drugs such as simvastatin, felodipine, and cyclosporin [34,35,36]. To the best of our knowledge, there have been no previous studies that have evaluated the inhibitory effects of honokiol on human CYP and UGT enzymes. The effect of honokiol on the activity of eight major human CYPs and four major human UGTs were examined using pooled human liver microsomes to evaluate the possibility of honokiol-drug interactions
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