trans-Stilbene oxide induces expression of genes involved in metabolism and transport in mouse liver via CAR and Nrf2 transcription factors

A. L. Slitt, Nathan J Cherrington, M. Z. Dieter, L. M. Aleksunes, G. L. Scheffer, W. Huang, D. D. Moore, C. D. Klaassen

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

trans-Stilbene oxide (TSO) induces drug metabolizing enzymes in rat and mouse liver. TSO is considered a phenobarbital-like compound because it induces Cyp2B mRNA expression in liver. Phenobarbital increases Cyp2B expression in liver via activation of the constitutive androstane receptor (CAR). The purpose of this study was to determine whether TSO induces gene expression in mouse liver via CAR activation. TSO increased CAR nuclear localization in mouse liver, activated the human Cyp2B6 promoter in liver in vivo, and activated a reporter plasmid that contains five nuclear receptor 1 (NR1) binding sites in HepG2 cells. TSO administration increased expression of Cyp2b10, NAD(P)H:quinone oxidoreductase (Nqo1), epoxide hydrolase, heme oxygenase-1, UDP- glucuronosyltransferase (Ugt) 1a6 and 2b5, and multidrug resistance-associated proteins (Mrp) 2 and 3 mRNA in livers from male mice. Cyp2b10 and epoxide hydrolase induction by TSO was decreased in livers from CAR-null mice, compared with wild-type mice, suggesting CAR involvement. In contrast, TSO administration induced Nqo1 and Mrp3 mRNA expression equally in livers from wild-type and CAR-null mice, suggesting that TSO induces expression of some genes through a mechanism independent of CAR. TSO increased nuclear staining of the transcription factor Nrf2 in liver, and activated an antioxidant/electrophile response element luciferase reporter construct that was transfected into HepG2 cells. In summary, in mice, TSO increases Cyp2b10 and epoxide hydrolase expression in mice via CAR, and potentially induces Nqo1 and Mrp3 expression via Nrf2. Moreover, our data demonstrate that a single compound can activate both CAR and Nrf2 transcription factors in liver.

Original languageEnglish (US)
Pages (from-to)1554-1563
Number of pages10
JournalMolecular Pharmacology
Volume69
Issue number5
DOIs
StatePublished - May 2006

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Transcription Factors
Gene Expression
Liver
Epoxide Hydrolases
Antioxidant Response Elements
Hep G2 Cells
Phenobarbital
Messenger RNA
stilbene oxide
constitutive androstane receptor
Glucuronosyltransferase
Heme Oxygenase-1
Cytoplasmic and Nuclear Receptors
Luciferases
NAD
Oxidoreductases
Plasmids
Binding Sites
Staining and Labeling
Enzymes

ASJC Scopus subject areas

  • Pharmacology

Cite this

trans-Stilbene oxide induces expression of genes involved in metabolism and transport in mouse liver via CAR and Nrf2 transcription factors. / Slitt, A. L.; Cherrington, Nathan J; Dieter, M. Z.; Aleksunes, L. M.; Scheffer, G. L.; Huang, W.; Moore, D. D.; Klaassen, C. D.

In: Molecular Pharmacology, Vol. 69, No. 5, 05.2006, p. 1554-1563.

Research output: Contribution to journalArticle

Slitt, A. L. ; Cherrington, Nathan J ; Dieter, M. Z. ; Aleksunes, L. M. ; Scheffer, G. L. ; Huang, W. ; Moore, D. D. ; Klaassen, C. D. / trans-Stilbene oxide induces expression of genes involved in metabolism and transport in mouse liver via CAR and Nrf2 transcription factors. In: Molecular Pharmacology. 2006 ; Vol. 69, No. 5. pp. 1554-1563.
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abstract = "trans-Stilbene oxide (TSO) induces drug metabolizing enzymes in rat and mouse liver. TSO is considered a phenobarbital-like compound because it induces Cyp2B mRNA expression in liver. Phenobarbital increases Cyp2B expression in liver via activation of the constitutive androstane receptor (CAR). The purpose of this study was to determine whether TSO induces gene expression in mouse liver via CAR activation. TSO increased CAR nuclear localization in mouse liver, activated the human Cyp2B6 promoter in liver in vivo, and activated a reporter plasmid that contains five nuclear receptor 1 (NR1) binding sites in HepG2 cells. TSO administration increased expression of Cyp2b10, NAD(P)H:quinone oxidoreductase (Nqo1), epoxide hydrolase, heme oxygenase-1, UDP- glucuronosyltransferase (Ugt) 1a6 and 2b5, and multidrug resistance-associated proteins (Mrp) 2 and 3 mRNA in livers from male mice. Cyp2b10 and epoxide hydrolase induction by TSO was decreased in livers from CAR-null mice, compared with wild-type mice, suggesting CAR involvement. In contrast, TSO administration induced Nqo1 and Mrp3 mRNA expression equally in livers from wild-type and CAR-null mice, suggesting that TSO induces expression of some genes through a mechanism independent of CAR. TSO increased nuclear staining of the transcription factor Nrf2 in liver, and activated an antioxidant/electrophile response element luciferase reporter construct that was transfected into HepG2 cells. In summary, in mice, TSO increases Cyp2b10 and epoxide hydrolase expression in mice via CAR, and potentially induces Nqo1 and Mrp3 expression via Nrf2. Moreover, our data demonstrate that a single compound can activate both CAR and Nrf2 transcription factors in liver.",
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AU - Slitt, A. L.

AU - Cherrington, Nathan J

AU - Dieter, M. Z.

AU - Aleksunes, L. M.

AU - Scheffer, G. L.

AU - Huang, W.

AU - Moore, D. D.

AU - Klaassen, C. D.

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