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First published on April 17, 2007; DOI: 10.1124/mol.106.033480

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Received for publication December 15, 2006.
Revised April 14, 2007.
Accepted for publication April 17, 2007.

Regulation of cytochrome P450 2E1 under hypertonic environment through TonEBP in human hepatocytes

Takashi Ito 1, Koko Asakura 1, Katsuhiko Tougou 1, Tsuyoshi Fukuda 1, Ryuji Kubota 1, Shinpei Nonen 1, Yasushi Fujio 1, Junichi Azuma 1*

1 Osaka university

* Address correspondence to: E-mail: azuma{at}phs.osaka-u.ac.jp

Abstract

Whereas the liver as well as the other organs is 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 controlled dependent on osmotic change in the liver. In the present study, we identified that CYP2E1 is induced under hypertonic environments at a transcriptional level in human primary hepatocytes, as assessed by cDNA microarray and real time-RT-PCR analyses. Consistently, both a protein level and the catalytic activity of CYP2E1 were increased in response to hypertonic condition. 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. Importantly, 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, co-transfection 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.


Key words: NFAT, Promoter analysis, Cytochrome P450, Regulation - transcriptional


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