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Research ArticleArticle

Regulation of Cytochrome P450 2E1 under Hypertonic Environment through TonEBP in Human Hepatocytes

Takashi Ito, Koko Asakura, Katsuhiko Tougou, Tsuyoshi Fukuda, Ryuji Kubota, Shinpei Nonen, Yasushi Fujio and Junichi Azuma
Molecular Pharmacology July 2007, 72 (1) 173-181; DOI: https://doi.org/10.1124/mol.106.033480
Takashi Ito
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Koko Asakura
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Katsuhiko Tougou
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Tsuyoshi Fukuda
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Ryuji Kubota
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Shinpei Nonen
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Yasushi Fujio
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Junichi Azuma
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Abstract

Whereas the liver as well as the other organs are continually exposed to the change of osmotic status, it has never been investigated whether activities and gene expressions of drug-metabolizing enzymes, including cytochromes P450, are dependent on osmotic change in the liver. In the present study, we determined that CYP2E1 is induced under hypertonic environments at a transcriptional level in human primary hepatocytes, as assessed by cDNA microarray and real time-reverse transcription-polymerase chain reaction analyses. Both a protein level and the catalytic activity of CYP2E1 were consistently increased in response to hypertonic conditions. In promoter-reporter assay, it was demonstrated that -586 to -566 in the CYP2E1 5′-flanking region was necessary for 2E1 promoter activation by hypertonic stimulation. It is noteworthy that tonicity-response element (TonE) consensus sequence was found at -578 to -568 in human CYP2E1 5′-flanking region, and electrophoretic mobility shift assay demonstrated the interaction of TonE binding protein (TonEBP) with TonE motif of CYP2E1 promoter. Furthermore, cotransfection of a CYP2E1 promoter construct with wild-type TonEBP expression vector enhanced promoter activity under both isotonic and hypertonic conditions, whereas dominant-negative TonEBP suppressed an induction of CYP2E1 promoter activity. These results indicate that the level of CYP2E1 is induced by hypertonic condition via TonEBP transactivation. The present study suggests that osmotic status may influence individual responses to the substrate of CYP2E1.

Footnotes

  • This study was supported in part by Grants-in-Aid from the Ministry of Health, Labor and Welfare and from the Ministry of Education, Science, Sports and Culture of Japan. This study was also support in part by Taisho Pharmaceutical Ltd, Takeda Science Foundation, The Salt Science Research Foundation (grant 0722) and The Nakatomi Foundation.

  • ABBREVIATIONS: P450, cytochrome P450; TonEBP, tonicity-response element binding protein; EMSA, electrophoretic mobility shift assay; PCR, polymerase chain reaction; SSC, standard saline citrate; RT, reverse transcription; TonE, tonicity-response element; SV40, simian virus 40; CMV, cytomegalovirus; dnTonEBP, dominant-negative TonEBP; HEK, human embryonic kidney; UGT, UDP glucuronosyltransferase; NAT, N-acetyl-transferase; SULT, sulfotransferase; GST, glutathione transferase; NFκB, nuclear factor κB; NFAT, nuclear factor of activated T cells; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RT-PCR, reverse transcription-polymerase chain reaction; EMSA, electrophoretic mobility shift assay; TauT, taurine transporter.

    • Received December 15, 2006.
    • Accepted April 17, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (1)
Molecular Pharmacology
Vol. 72, Issue 1
1 Jul 2007
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Research ArticleArticle

Regulation of Cytochrome P450 2E1 under Hypertonic Environment through TonEBP in Human Hepatocytes

Takashi Ito, Koko Asakura, Katsuhiko Tougou, Tsuyoshi Fukuda, Ryuji Kubota, Shinpei Nonen, Yasushi Fujio and Junichi Azuma
Molecular Pharmacology July 1, 2007, 72 (1) 173-181; DOI: https://doi.org/10.1124/mol.106.033480

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Research ArticleArticle

Regulation of Cytochrome P450 2E1 under Hypertonic Environment through TonEBP in Human Hepatocytes

Takashi Ito, Koko Asakura, Katsuhiko Tougou, Tsuyoshi Fukuda, Ryuji Kubota, Shinpei Nonen, Yasushi Fujio and Junichi Azuma
Molecular Pharmacology July 1, 2007, 72 (1) 173-181; DOI: https://doi.org/10.1124/mol.106.033480
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