title: Different AhR binding sites of diterpenoid ligands from Andrographis paniculata caused differential CYP1A1 induction in primary culture in mouse hepatocytes.
abstract: Andrographis paniculata has been employed as a folklore remedy. Andrographolide (Andro), 14-deoxy-11,12-didehydroandrographolide (DHA), andrographiside (AS), and neoandrographolide (Neo), are major diterpenoids isolated from this plant. In the present study, influence of the four diterpenoids on CYP1A1 mRNA expression was investigated in primary cultured mouse hepatocytes. Additionally, binding of these compounds to aryl hydrocarbon receptor (AhR) was examined using molecular docking analysis to clarify mechanism of CYP1A1 induction. Andro and DHA induced CYP1A1 expression by itself, and co-treatment with a CYP1A1 inducer (BNF, beta-naphthoflavone) showed a synergistic increase of CYP1A1 expression. Andro demonstrated higher enhancing activity than DHA at every similar concentration. On the other hand, Neo suppressed BNF-induced CYP1A1 expression, but AS did not modify the induction. Results from molecular docking analysis of BNF and four diterpenoids on ligand binding domain of AhR were consistent with levels of CYP1A1 mRNA expressions. Furthermore, difference of binding sites of BNF in the presence of diterpenoids might affect the synergism or inhibition of CYP1A1 expression. These results suggest that use of A. paniculata as a health supplement should be concerned in term of herb-drugs interactions or risk of carcinogenesis, according to its ability to influence CYP1A1 expression.
authors.affiliation: Faculty of Pharmaceutical Sciences, Khon Kaen University, Mittrapharb Road, Muang, Khon Kaen 40002, Thailand.
authors.forename: Waranya
authors.initials: W
authors.lastname: Chatuphonprasert
authors.forename: Tawun
authors.initials: T
authors.lastname: Remsungnen
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nemoto
authors.forename: Kanokwan
authors.initials: K
authors.lastname: Jarukamjorn
mesh_terms: D035685:Andrographis; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D041743:Herb-Drug Interactions; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008968:Molecular Conformation; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000378:metabolism*; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D004224:Diterpenes; D008024:Ligands; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1