title: Evaluation of in vitro cytochrome P450 induction and inhibition activity of deoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber L.
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.
authors.affiliation: Malaysian Institute of Pharmaceuticals & Nutraceuticals, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang, Malaysia.
authors.forename: Xue Fen
authors.initials: XF
authors.lastname: Koe
authors.forename: Ee Lin
authors.initials: EL
authors.lastname: Lim
authors.forename: Tiong Chai
authors.initials: TC
authors.lastname: Seah
authors.forename: Azimah
authors.initials: A
authors.lastname: Amanah
authors.forename: Habibah Abdul
authors.initials: HA
authors.lastname: Wahab
authors.forename: Mohd Ilham
authors.initials: MI
authors.lastname: Adenan
authors.forename: Shaida Fariza
authors.initials: SF
authors.lastname: Sulaiman
authors.forename: Mei Lan
authors.initials: ML
authors.lastname: Tan
mesh_terms: D019659:Asteraceae / Q000737:chemistry*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007783:Lactones / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000633:toxicity*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D007783:Lactones; D012333:RNA, Messenger; D012717:Sesquiterpenes; C528427:deoxyelephantopin; D049452:Green Fluorescent Proteins; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4; Cytochrome P450 induction assay; Cytochrome P450 inhibition assay; Deoxyelephantopin; Drug–herb interactions