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Drug Metabolism and Disposition Fast Forward
First published on April 18, 2006; DOI: 10.1124/dmd.105.007542

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Received for publication December 29, 2005.
Revised April 4, 2006.
Accepted for publication April 12, 2006.

Induction of genes for metabolism and transport by trans-stilbene oxide in livers of Sprague-Dawley and Wistar-Kyoto Rats

Angela L Slitt 1, Nathan Cherrington 2, Craig Fisher 2, Masahiko Negishi 3, Curtis D. Klaassen 1*

1 University of Kansas Medical Center 2 University of Arizona 3 NIEHS, NIH

* Address correspondence to: E-mail: cklaasse{at}kumc.edu

Abstract

Trans-stilbene oxide (TSO) is a synthetic pro-estrogen that induces phase-I and -II drug metabolizing enzymes in rat liver. The purpose of this study was to determine whether TSO also induces transporter expression in rat liver and whether gene induction in rat liver after TSO occurs in a constitutive androstane receptor (CAR)-dependent manner. Total RNA was isolated from male rat livers after treatment with TSO for up to 4 days (200 mg/kg, ip, twice daily) and the mRNA levels for each gene were quantified. CYP2B1/2, CYP3A1, Epoxide Hydrolase, Heme Oxygenase-1, UGT1A6, UGT2B1, Multiple drug resistance protein (Mdr) 1a and 1b, as well as Multidrug resistance-associated protein (Mrp) 2, 3, and 4 mRNAs were increased in livers after TSO treatment. To determine whether TSO activates gene expression in a CAR-dependent manner, male and female Wistar Kyoto rats were treated with TSO for 3 days. TSO induced CYP2B1/2, UGT2B1, and Mdr1b in males more than in females, suggesting that TSO could increase their expression via CAR. Conversely, TSO induced CYP3A1, Epoxide Hydrolase, UGT1A6, and Mrp3 similarly in both genders, indicating that induction of these genes occurs independently of CAR. TSO treatment also increased the activity of a CAR binding element luciferase reporter construct in HepG2 cells transfected with rat CAR and in mouse liver. Additionally, TSO increased antioxidant response element/electrophile response element luciferase reporter construct activity in HepG2 cells. In conclusion, in WKY rat liver, TSO increases CYP2B1/2, UGT2B1, and Mdr1b mRNA expression in a gender-dependent manner and CYP3A1, Epoxide Hydrolase, UGT1A6, and Mrp3 in a gender-independent manner.


Key words: ABC transporters, CAR, CYP2B, epoxide hydrolase, heme oxygenases, NAD(P)H-quinone oxidoreductase, nuclear receptors, transporters, UDP glucuronyltransferases




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