Abstract
trans-Stilbene oxide (TSO) is a synthetic proestrogen 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, i.p., 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 mRNA were increased in livers after TSO treatment. To determine whether TSO activates gene expression in a CAR-dependent manner, male and female Wistar-Kyoto (WKY) 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.
Footnotes
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This work was supported by National Institutes of Health Grants ES-09716, ES-07079, and ES-11239 (A.L.S., N.J.C.).
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This work was presented, in part, at the 2003 Annual Society of Toxicology Meeting in Salt Lake City, UT.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007542.
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ABBREVIATIONS: TSO, trans-stilbene oxide; PB, phenobarbital; NQO1, NAD(P)H:quinone oxidoreductase 1; UGT, UDP-glucuronosyltransferase(s); Mrp, multidrug resistance-associated protein; CAR, constitutive androstane receptor; NR1, nuclear receptor binding site 1; bp, base pair(s); PBREM, phenobarbital response element module; WKY, Wistar-Kyoto; Mdr, multiple drug resistance protein; bDNA, branched DNA signal amplification; PBS, phosphate-buffered saline; ARE/EpRE, antioxidant response element/electrophile response element; DMSO, dimethyl sulfoxide; PXR, pregnane X receptor; Nrf2, nuclear factor E2-related factor 2; RLU, relative light units.
- Received December 28, 2005.
- Accepted April 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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