Presence on human chromosome 10 of omeprazole-sensitivity gene whose product mediates CYP1A1 induction

Kikuchi, Hideaki; Fukushige, Shinichi; Shibazaki, Masahiko; Shiratori, Yoshimune

doi:10.1159/000064040

Cited by 6 publications

(6 citation statements)

References 27 publications

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“…The species-specific differences in AhR activation by OME are thought to result from intracellular environment but not AhR itself (Kikuchi et al, 2002). The insensitivity to OME in mouse hepatocyte and OME reactivity of mouse AhR expressed in yeast agreed with this theory (Dzeletovic et al, 1997), and were reconfirmed in this study.…”

Section: Discussionsupporting

confidence: 78%

Microbial Metabolites of Omeprazole Activate Murine Aryl Hydrocarbon Receptor In Vitro and In Vivo

Shiizaki

Kawanishi

Yagi

2014

Drug Metabolism and Disposition

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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 a-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.

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Section: Discussionsupporting

confidence: 78%

Microbial Metabolites of Omeprazole Activate Murine Aryl Hydrocarbon Receptor In Vitro and In Vivo

Shiizaki

Kawanishi

Yagi

2014

Drug Metabolism and Disposition

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“…SB203580 Suppresses CYP1A1-mRNA Induction by Omeprazole-Kikuchi et al (27) showed that omeprazole induced CYP1A1-mRNA in a ligand-independent manner, and that the gene(s) that mediate its induction are present on human chromosome 10p (27). The induction of CYP1A1-mRNA by omeprazole was not suppressed by the AhR antagonist PD98059, suggesting the existence of a ligand-independent signaling pathway (Fig.…”

Section: Sb203580 Does Not Suppress In Vitro Ahrmentioning

confidence: 93%

“…Therefore, PI compounds are not acting as simple AhR antagonists. Kikuchi et al (27,33) have shown that omeprazole, an inhibitor of H ϩ /K ϩ -ATPase, activates AhR in a ligand-independent way. Our Fig.…”

Section: Sb203580 Does Not Suppress Translocation Of Ahr To the Nuclementioning

confidence: 99%

Suppression by p38 MAP Kinase Inhibitors (Pyridinyl Imidazole Compounds) of Ah Receptor Target Gene Activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and the Possible Mechanism

Shibazaki

Takeuchi

Ahmed

et al. 2004

Journal of Biological Chemistry

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Cytochrome P-450 1A1 (CYP1A1) is known to be induced by aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), through activation of the aryl hydrocarbon receptor (AhR). We found that p38 MAP kinase inhibitors (SB203580 and SB202190; 40 M each; pyridinyl imidazole compounds) suppressed CYP1A1-mRNA induction by TCDD (2 nM) in mouse hepatoma Hepa-1 cells and in human hepatoma HepG2 cells, and also suppressed CYP1B1-mRNA induction by TCDD (2 nM) in human breast adenocarcinoma MCF7 cells. An analogue compound, SB202474, which does not inhibit p38 MAP kinase, also suppressed CYP1A1-mRNA induction by TCDD. Moreover, overexpression of a dominantnegative gene for p38 MAP kinase in Hepa-1 cells did not suppress Cyp1a1 reporter gene induction by TCDD. Therefore, the suppression of Cyp1a1 transcription by pyridinyl imidazole compounds is not because of their inhibition of p38 MAP kinase activity. Because SB203580 did not inhibit in vitro AhR transformation by TCDD, this compound was not acting as a simple AhR antagonist. SB203580 decreased TCDD-induced histone acetylation levels in the region of the Cyp1a1 gene promoter, especially around the TATA box sequence. This result suggests the possibility that pyridinyl imidazole compounds suppress the recruitment of some co-activator that has the histone acetyltransferase activity necessary for CYP1A1-mRNA transcription.

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“…However, the PTK pathway appears to be unrelated to this interspecies difference because the tyrosine 320 residue is conserved in mouse and human AhRs. By fusing mouse and human hepatoma cells, a gene locus was assigned as a humanspecific gene responsible for CYP1A1 induction by OME (Kikuchi et al, 2002). However, specific genes exhibiting response to OME have not been identified.…”

Section: Introductionmentioning

confidence: 99%

Identification of Amino Acid Residues in the Ligand-Binding Domain of the Aryl Hydrocarbon Receptor Causing the Species-Specific Response to Omeprazole: Possible Determinants for Binding Putative Endogenous Ligands

Shiizaki

Ohsako

Kawanishi

et al. 2014

Molecular Pharmacology

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Omeprazole (OME) induces the expression of genes encoding drug-metabolizing enzymes, such as CYP1A1, via activation of the aryl hydrocarbon receptor (AhR) both in vivo and in vitro. However, the precise mechanism of OME-mediated AhR activation is still under investigation. While elucidating speciesspecific susceptibility to dioxin, we found that OME-mediated AhR activation was mammalian species specific. Moreover, we previously reported that OME has inhibitory activity toward CYP1A1 enzymes. From these observations, we speculated that OME-mediated AhR target gene transcription is due to AhR activation by increasing amounts of putative AhR ligands in serum by inhibition of CYP1A1 activity. We compared the amino acid sequences of OME-sensitive rabbit AhR and nonsensitive mouse AhR to identify the residues responsible for the species-specific response. Chimeric AhRs were constructed by exchanging domains between mouse and rabbit AhRs to define the region required for the response to OME. OME-mediated transactivation was observed only with the chimeric AhR that included the ligandbinding domain (LBD) of the rabbit AhR. Site-directed mutagenesis revealed three amino acids (M328, T353, and F367) in the rabbit AhR that were responsible for OME-mediated transactivation. Replacing these residues with those of the mouse AhR abolished the response of the rabbit AhR. In contrast, substitutions of these amino acids with those of the rabbit AhR altered nonsensitive mouse AhR to become sensitive to OME. These results suggest that OME-mediated AhR activation requires a specific structure within LBD that is probably essential for binding with enigmatic endogenous ligands.

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Presence on human chromosome 10 of omeprazole-sensitivity gene whose product mediates CYP1A1 induction

Cited by 6 publications

References 27 publications

Microbial Metabolites of Omeprazole Activate Murine Aryl Hydrocarbon Receptor In Vitro and In Vivo

Microbial Metabolites of Omeprazole Activate Murine Aryl Hydrocarbon Receptor In Vitro and In Vivo

Suppression by p38 MAP Kinase Inhibitors (Pyridinyl Imidazole Compounds) of Ah Receptor Target Gene Activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and the Possible Mechanism

Identification of Amino Acid Residues in the Ligand-Binding Domain of the Aryl Hydrocarbon Receptor Causing the Species-Specific Response to Omeprazole: Possible Determinants for Binding Putative Endogenous Ligands

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