title: Microbial metabolites of omeprazole activate murine aryl hydrocarbon receptor in vitro and in vivo.
abstract: Omeprazole (OME), a proton pump inhibitor used to treat gastritis, is also an aryl hydrocarbon receptor (AhR) activator. OME activates AhR in human hepatocytes and hepatoma cells, but not in mice in vivo or in vitro. We recently discovered that this species-specific difference results from a difference in a few amino acids in the ligand-binding domain of AhR. However, OME activates both mouse and human AhRs in the yeast reporter assay system. Nevertheless, the cause of this discrepancy in OME responses remains unknown. Here, we report that CYP1A1 mRNA expression in mouse cecum was elevated after OME administration, although the mouse is regarded as an OME-unresponsive animal. Using the yeast reporter assay system with human and murine AhRs, we found AhR agonist-like activity in the cecal extracts of OME-treated mice. We speculated that OME metabolites produced by cecal bacteria might activate murine AhRs in vivo. In high-performance liquid chromatography (HPLC) analysis, AhR agonist-like activity of cecal bacterial culture and cecal extracts were detected at the same retention time. AhR agonist-like activity was also detected in the HPLC fractions of yeast culture media containing OME. This unknown substance could induce reporter gene expression via mouse and human AhRs. The agonist-like activity of the OME metabolite was reduced by concomitant α-naphthoflavone exposure. These results indicate that a yeast-generated OME metabolite elicited the response of mouse AhR to OME in the yeast system, and that bacterial OME metabolites may act as AhR ligands in human and mouse intestines.
authors: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan (K.S.); Department of Biology, Graduate School of Science, Osaka Prefecture University, Osaka, Japan (M.K., T.Y.); and Department of Life Science, Dongguk University, Seoul, South Korea (T.Y.).
authors: Kazuhiro
authors: K
authors: Shiizaki
authors: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan (K.S.); Department of Biology, Graduate School of Science, Osaka Prefecture University, Osaka, Japan (M.K., T.Y.); and Department of Life Science, Dongguk University, Seoul, South Korea (T.Y.).
authors: Masanobu
authors: M
authors: Kawanishi
authors: Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan (K.S.); Department of Biology, Graduate School of Science, Osaka Prefecture University, Osaka, Japan (M.K., T.Y.); and Department of Life Science, Dongguk University, Seoul, South Korea (T.Y.) yagi-t@riast.osakafu-u.ac.jp.
authors: Takashi
authors: T
authors: Yagi
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists*; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002432:Cecum / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D002478:Cells, Cultured; D003470:Culture Media / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D009853:Omeprazole / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001571:Benzoflavones; D003470:Culture Media; D019363:Cytochrome P-450 CYP1A1; D009853:Omeprazole; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C484722:Ahr protein, mouse; C011512:alpha-naphthoflavone