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Molecular Pharmacology

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Research ArticleArticle

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

Kazuhiro Shiizaki, Seiichiroh Ohsako, Masanobu Kawanishi and Takashi Yagi
Molecular Pharmacology February 2014, 85 (2) 279-289; DOI: https://doi.org/10.1124/mol.113.088856
Kazuhiro Shiizaki
Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan (K.S.); Division of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (S.O.); Department of Life Science, Dongguk University, Seoul, Korea (T.Y.); and Department of Biology, Graduate School of Science, Osaka Prefecture University, Osaka, Japan (M.K., T.Y.)
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Seiichiroh Ohsako
Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan (K.S.); Division of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (S.O.); Department of Life Science, Dongguk University, Seoul, Korea (T.Y.); and Department of Biology, Graduate School of Science, Osaka Prefecture University, Osaka, Japan (M.K., T.Y.)
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Masanobu Kawanishi
Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan (K.S.); Division of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (S.O.); Department of Life Science, Dongguk University, Seoul, Korea (T.Y.); and Department of Biology, Graduate School of Science, Osaka Prefecture University, Osaka, Japan (M.K., T.Y.)
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Takashi Yagi
Division of Cancer Development System, National Cancer Center Research Institute, Tokyo, Japan (K.S.); Division of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (S.O.); Department of Life Science, Dongguk University, Seoul, Korea (T.Y.); and Department of Biology, Graduate School of Science, Osaka Prefecture University, Osaka, Japan (M.K., T.Y.)
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Abstract

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 species-specific 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 ligand-binding 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.

Footnotes

    • Received July 29, 2013.
    • Accepted November 21, 2013.
  • This research was supported by Grants-in-Aid for Scientific Research (S) [Grants 18101002, 18101003]; (C) [Grant 23590162] from MEXT Japan; and in part, by the Environmental Technology Development Fund to S.O. from the Ministry of the Environment.

  • dx.doi.org/10.1124/mol.113.088856.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (2)
Molecular Pharmacology
Vol. 85, Issue 2
1 Feb 2014
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Research ArticleArticle

AhR Amino Acid Residues Required for Response to Omeprazole

Kazuhiro Shiizaki, Seiichiroh Ohsako, Masanobu Kawanishi and Takashi Yagi
Molecular Pharmacology February 1, 2014, 85 (2) 279-289; DOI: https://doi.org/10.1124/mol.113.088856

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Research ArticleArticle

AhR Amino Acid Residues Required for Response to Omeprazole

Kazuhiro Shiizaki, Seiichiroh Ohsako, Masanobu Kawanishi and Takashi Yagi
Molecular Pharmacology February 1, 2014, 85 (2) 279-289; DOI: https://doi.org/10.1124/mol.113.088856
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