title: Andrographolide and 14-deoxy-11, 12-didehydroandrographolide inhibit cytochrome P450s in HepG2 hepatoma cells.
abstract: OBJECTIVE
  Cytochrome P450 (CYP) enzymes have been implicated in a large number of preventable drug-herb interactions. Andrographis paniculata Nees, a tropical herb widely used for various health conditions contains two major diterpenoids, andrographolide and 14-Deoxy-11, 12-Didehydroandrographolide. These compounds were evaluated systematically for their effects on CYP1A2, CYP2D6 and CYP3A4 expressions in HepG2 cells.
  
  
  METHODS
  Quantitative RT-PCR and Western blot analysis were used to assess the mRNA and protein expression of the three CYPs. CYP3A4 enzyme activity was evaluated using P450-Glo™ Assays. The LanthaScreen® TR-FRET PXR (SXR) Competitive Binding Assay was used to determine if the compounds are potential PXR-ligands.
  
  
  RESULTS
  Both diterpenoids inhibited the mRNA and protein expressions of CYP1A2, CYP2D6, and CYP3A4. Interestingly, the lowest concentration of both diterpenoids produced a more than 50% reduction in the mRNA and protein expression of CYP3A4 and this reduction was consistent with the enzyme activity. Further experiments revealed that both diterpenoids were also capable of attenuating the ability of dexamethasone to induce CYP3A4 expression, and 14-Deoxy-11, 12-Didehydroandrographolide tended to bind to the PXR-LBD site in a concentration-dependent manner.
  
  
  CONCLUSIONS
  These diterpenoids are potential CYP3A4 inhibitors and the effects on CYP3A4 may be clinically significant. 14-Deoxy-11, 12-Didehydroandrographolide inhibits CYP3A4 by binding and antagonizing PXR function.
authors.affiliation: Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
authors.forename: Jer Ping
authors.initials: JP
authors.lastname: Ooi
authors.forename: Masanori
authors.initials: M
authors.lastname: Kuroyanagi
authors.forename: Shaida Fariza
authors.initials: SF
authors.lastname: Sulaiman
authors.forename: Tengku Sifzizul Tengku
authors.initials: TS
authors.lastname: Muhammad
authors.forename: Mei Lan
authors.initials: ML
authors.lastname: Tan
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C495626:14-deoxy-11,12-didehydroandrographolide; D065607:Cytochrome P-450 Enzyme Inhibitors; D004224:Diterpenes; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C030419:andrographolide; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System