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  • Title: Selective inhibitory effects of machilin A isolated from Machilus thunbergii on human cytochrome P450 1A and 2B6.
    Author: Kim SJ, You J, Choi HG, Kim JA, Jee JG, Lee S.
    Journal: Phytomedicine; 2015 Jun 01; 22(6):615-20. PubMed ID: 26055126.
    Abstract:
    BACKGROUND: The bark of Machilus thunbergii (Lauraceae) has been used as a folk medicine to treat abdominal pain and distension, and leg edema in Korea. Machilin A (MA), a lignan isolated from Machilus thunbergii, exhibits several biological activities including anti-oxidant and stimulatory effects on cell differentiation and proliferation. PURPOSE: Potential drug-interactions with MA via inhibition of cytochrome P450 (CYP) activity in human liver microsomes (HLMs), have not been investigated. STUDY DESIGN: The inhibitory effects of MA on the activities of CYPs were investigated using cocktail probe substrates in pooled HLMs and on human recombinant cDNA-expressed CYP isoforms. METHODS: The nine CYP-specific substrates were incubated in HLM or recombinant cDNA-expressed CYP 1A1, 1A2 and 2B6 with MA. After incubation, the samples were injected onto a C18 column for liquid chromatography-tandem mass spectrometry analysis. To investigate the binding poses between MA and CYP, we carried out structure-based docking simulations by using software and scripts written in-house (ALIS-DOCK; Automatic pLatform for Iterative Structure-based DOCKing). RESULTS: MA strongly inhibited CYP1A2-mediated phenacetin O-deethylation and CYP2B6-mediated bupropion hydroxylation with IC50 values of 3.0 and 3.9 µM, respectively, while it did not significantly inhibit other CYPs. A Dixon plot indicated that MA competitively inhibits CYP1A2 and CYP2B6 with Ki values of 0.71 and 4.1 µM, respectively. CONCLUSION: Overall, this was the first investigation of the inhibitory effects of MA on CYP1A2 and CYP2B6 in HLMs, and it has identified that MA acts via competitive inhibition.
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