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Research ArticleArticle

FUNCTIONAL ANALYSIS OF SIX HUMAN ARYL HYDROCARBON RECEPTOR VARIANTS IN A JAPANESE POPULATION

Satoru Koyano, Yoshiro Saito, Hiromi Fukushima-Uesaka, Seiichi Ishida, Shogo Ozawa, Naoyuki Kamatani, Hironobu Minami, Atsushi Ohtsu, Tetsuya Hamaguchi, Kuniaki Shirao, Teruhiko Yoshida, Nagahiro Saijo, Hideto Jinno and Jun-Ichi Sawada
Drug Metabolism and Disposition August 2005, 33 (8) 1254-1260; DOI: https://doi.org/10.1124/dmd.105.004655
Satoru Koyano
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Yoshiro Saito
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Hiromi Fukushima-Uesaka
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Seiichi Ishida
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Shogo Ozawa
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Naoyuki Kamatani
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Hironobu Minami
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Atsushi Ohtsu
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Tetsuya Hamaguchi
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Kuniaki Shirao
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Teruhiko Yoshida
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Nagahiro Saijo
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Hideto Jinno
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Jun-Ichi Sawada
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Abstract

Aryl hydrocarbon receptor (AhR) is an important transcriptional regulator involved in the induction of CYP1A1, CYP1A2, CYP1B1, UGT1A1, and UGT1A6. In this study, functional properties of four novel naturally occurring human AhR variants (K401R, N487D, I514T, and K17T/R554K) were examined along with the single variants K17T and R554K. The luciferase reporter assay using the CYP1A1 promoter reporter in HeLa cells treated with β-naphthoflavone or 3-methylcholanthrene, which are known as typical agonists for AhR, showed that reporter activities of the K401R and N487D variants were reduced to 40 to 58% of those of wild-type (WT) but not of the other variants. Similarly, the K401R and N487D variants also reduced the omeprazole-induced reporter activities to approximately 56 and 74% of those of the WT, respectively. The reduced activities of the two variants were probably caused by the reduced protein expression levels, since the protein levels of the K401R and N487D variants were approximately 52 and 47% of the WT, respectively, without any changes in their mRNA levels. The reduced protein levels were recovered by treatment with a proteasome inhibitor MG132 [N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal], suggesting that the reduced protein levels were caused by the accelerated proteasomal degradation by a proteasome. Together, the current data demonstrate that the K401R and N487D variants reduce their apparent transcriptional activities, both ligand-induced and omeprazole-induced activation, probably through reduced protein expression. Thus, these two variants may influence drug metabolism through reduced induction of CYP1A1 and other target enzymes.

Footnotes

  • This study was supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences (MPJ-1 and -6) of the Pharmaceuticals and Medical Devices Agency of Japan.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.004655.

  • ABBREVIATIONS: AhR, aryl hydrocarbon receptor; Arnt, aryl hydrocarbon receptor nuclear translocator; XRE, xenobiotic responsive element; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; 3MC, 3-methylcholanthrene; BNF, β-naphthoflavone; SNP, single nucleotide polymorphism; PCR, polymerase chain reaction; hAhR, human aryl hydrocarbon receptor; hArnt, human aryl hydrocarbon receptor nuclear translocator; OME, omeprazole; RT-PCR, reverse transcription-polymerase chain reaction; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; WT, wild-type; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; PLSD, protected least significant difference.

    • Received March 6, 2005.
    • Accepted April 27, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (8)
Drug Metabolism and Disposition
Vol. 33, Issue 8
1 Aug 2005
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Research ArticleArticle

FUNCTIONAL ANALYSIS OF SIX HUMAN ARYL HYDROCARBON RECEPTOR VARIANTS IN A JAPANESE POPULATION

Satoru Koyano, Yoshiro Saito, Hiromi Fukushima-Uesaka, Seiichi Ishida, Shogo Ozawa, Naoyuki Kamatani, Hironobu Minami, Atsushi Ohtsu, Tetsuya Hamaguchi, Kuniaki Shirao, Teruhiko Yoshida, Nagahiro Saijo, Hideto Jinno and Jun-Ichi Sawada
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1254-1260; DOI: https://doi.org/10.1124/dmd.105.004655

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Research ArticleArticle

FUNCTIONAL ANALYSIS OF SIX HUMAN ARYL HYDROCARBON RECEPTOR VARIANTS IN A JAPANESE POPULATION

Satoru Koyano, Yoshiro Saito, Hiromi Fukushima-Uesaka, Seiichi Ishida, Shogo Ozawa, Naoyuki Kamatani, Hironobu Minami, Atsushi Ohtsu, Tetsuya Hamaguchi, Kuniaki Shirao, Teruhiko Yoshida, Nagahiro Saijo, Hideto Jinno and Jun-Ichi Sawada
Drug Metabolism and Disposition August 1, 2005, 33 (8) 1254-1260; DOI: https://doi.org/10.1124/dmd.105.004655
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