title: Selective inhibitory effects of machilin A isolated from Machilus thunbergii on human cytochrome P450 1A and 2B6.
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.
  
  
  OBJECTIVE
  Potential drug-interactions with MA via inhibition of cytochrome P450 (CYP) activity in human liver microsomes (HLMs), have not been investigated.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daehak-ro 80, Daegu 702-701, South Korea.
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daehak-ro 80, Daegu 702-701, South Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: You
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daehak-ro 80, Daegu 702-701, South Korea.
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daehak-ro 80, Daegu 702-701, South Korea.
authors.forename: Jeong Ah
authors.initials: JA
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daehak-ro 80, Daegu 702-701, South Korea.
authors.forename: Jun-Goo
authors.initials: JG
authors.lastname: Jee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daehak-ro 80, Daegu 702-701, South Korea. Electronic address: sangkyu@knu.ac.kr.
authors.forename: Sangkyu
authors.initials: S
authors.lastname: Lee
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065702:Cytochrome P-450 CYP2B6 / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019770:Lauraceae / Q000737:chemistry*; D017705:Lignans / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D024301:Plant Bark / Q000737:chemistry; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D052117:Benzodioxoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D017705:Lignans; D011994:Recombinant Proteins; C539438:machilin A; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; C585599:CYP2B6 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6
keywords: Competitive inhibition; Cytochromes P450; Human liver microsomes; Machilin A; Machilus thunbergii