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      Evaluation of in vitro cytochrome P450 induction and inhibition activity of deoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber L.

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          Abstract

          Drug metabolism involving cytochrome P450 (CYP) enzymes is a key determinant of significant drug interactions. Deoxyelephantopin was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4, and protein expression and resultant enzymatic activity. The mRNA and protein expression of cytochrome isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis, respectively. Human CYP3A4 protein expression was determined using an optimized hCYP3A4-HepG2 cell-based assay and the enzymatic activity was evaluated using P450-Glo™ CYP3A4 assay. The molecular interaction and possible inhibition of deoxyelephantopin of the CYP3A4 enzyme was determined in silico and further validated using substrate-specific CYP3A4 inhibition assays. Deoxyelephantopin produced no significant effect on the CYP1A2 and CYP2D6 mRNA and protein expression. However, it has a weak induction effect on CYP3A4 at the transcriptional level. In silico docking simulation showed that deoxyelephantopin has a weak interaction with CYP3A4 enzyme and it minimally affects the metabolism of CYP3A4 substrates. Deoxyelephantopin is not an in vitro CYP1A2 and CYP2D6 inducer. It is both a weak in vitro CYP3A4 inducer and inhibitor and is unlikely to elicit a clinically significant effect in human.

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          Author and article information

          Journal
          Food Chem. Toxicol.
          Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
          Elsevier BV
          1873-6351
          0278-6915
          Oct 2013
          : 60
          Affiliations
          [1 ] Malaysian Institute of Pharmaceuticals & Nutraceuticals, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia.
          Article
          S0278-6915(13)00485-7
          10.1016/j.fct.2013.07.030
          23876819
          6d28062d-12c4-4c5b-82d3-bb55141627f7
          History

          CYP3A4,Cytochrome P450 induction assay,Cytochrome P450 inhibition assay,Deoxyelephantopin,Drug–herb interactions

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