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Drug Metabolism and Disposition Fast Forward
First published on May 12, 2008; DOI: 10.1124/dmd.108.020867

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Received for publication February 19, 2008.
Revised May 6, 2008.
Accepted for publication May 7, 2008.

THE Nrf2 ACTIVATOR OLTIPRAZ ALSO ACTIVATES THE CONSTITUTIVE ANDROSTANE RECEPTOR

Matthew D. Merrell 1, Jonathan P. Jackson 1, Lisa M. Augustine 1, Craig D. Fisher 1, Angela L. Slitt 2, Jonathan M. Maher 3, Wendong Huang 4, David D. Moore 4, Youcai Zhang 5, Curtis D. Klaassen 6, Nathan J. Cherrington 1*

1 University of Arizona 2 University of Rhode Island 3 University of Tsukuba Tennoudai 4 Baylor College of Medicine 5 University of Kansas 6 University of Kansas Medical Center

* Address correspondence to: E-mail: cherrington{at}pharmacy.arizona.edu

Abstract

Oltipraz (OPZ) is a well-known inducer of NAD(P)H:quinone oxidoreductase (NQO1) along with other enzymes that comprise the NF-E2-related factor2 (Nrf2) battery of detoxification genes. However, OPZ treatment also induces expression of CYP2B, a gene regulated by the constitutive androstane receptor (CAR). Therefore, this study was designed to determine whether OPZ induces gene expression in the mouse liver through activation of CAR in addition to Nrf2. OPZ increased the mRNA expression of both Cyp2b10 and Nqo1 in C57BL/6 mouse livers. As expected, in livers from Nrf2-/- mice, OPZ induction of Nqo1 was reduced, indicating Nqo1 induction is dependent on Nrf2 activation, whereas Cyp2b10 induction was unchanged. The robust induction of Cyp2b10 by OPZ in wild-type mice was completely absent in CAR-/- mice, revealing a CAR dependent induction by OPZ. OPZ also induced transcription of the human CYP2B6 promoter-reporter containing the phenobarbital responsive element in mouse liver using an in vivo transcription assay. Additionally, OPZ induced in vivo nuclear accumulation of CAR at 3 h, but, as with phenobarbital, was unable to reverse androstanol repression of mCAR constitutive activity in transiently transfected HepG2 cells. In summary, OPZ induces expression of Cyp2b10 and Nqo1 via the activation of CAR and Nrf2, respectively.


Key words: CAR, CYP2B, cytochrome P450 regulation, gene regulation, NAD(P)H-quinone oxidoreductase, RXR, transcriptional regulation




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