QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.014571v1 69/5/1554    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Slitt, A. L. Articles by Klaassen, C. D. Search for Related Content PubMed PubMed Citation Articles by Slitt, A. L. Articles by Klaassen, C. D.

trans-Stilbene Oxide Induces Expression of Genes Involved in Metabolism and Transport in Mouse Liver via CAR and Nrf2 Transcription Factors

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (A.L.S., M.Z.D., C.D.K.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (N.J.C.); Department of Pharmaceutical Sciences, University of Connecticut, Connecticut (L.M.A.); Department of Pathology, VU Medical Center, Vrije Universiteit, Amsterdam, The Netherlands (G.L.S.); and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (W.H., D.D.M.)

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-glucuronosyl-transferase (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.

Address correspondence to: Dr. Curtis Klaassen, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7417. E-mail: cklaasse{at}kumc.edu

This article has been cited by other articles:

				M. D. Merrell, J. P. Jackson, L. M. Augustine, C. D. Fisher, A. L. Slitt, J. M. Maher, W. Huang, D. D. Moore, Y. Zhang, C. D. Klaassen, et al. The Nrf2 Activator Oltipraz Also Activates the Constitutive Androstane Receptor Drug Metab. Dispos., August 1, 2008; 36(8): 1716 - 1721. [Abstract] [Full Text] [PDF]

				C. D. Fisher, L. M. Augustine, J. M. Maher, D. M. Nelson, A. L. Slitt, C. D. Klaassen, L. D. Lehman-McKeeman, and N. J. Cherrington Induction of Drug-Metabolizing Enzymes by Garlic and Allyl Sulfide Compounds via Activation of Constitutive Androstane Receptor and Nuclear Factor E2-Related Factor 2 Drug Metab. Dispos., June 1, 2007; 35(6): 995 - 1000. [Abstract] [Full Text] [PDF]

				W. Chen, S.-Y. Cai, S. Xu, L. A. Denson, C. J. Soroka, and J. L. Boyer Nuclear receptors RXR{alpha}:RAR{alpha} are repressors for human MRP3 expression Am J Physiol Gastrointest Liver Physiol, May 1, 2007; 292(5): G1221 - G1227. [Abstract] [Full Text] [PDF]

				A. L. Slitt, N. J. Cherrington, C. D. Fisher, M. Negishi, and C. D. Klaassen INDUCTION OF GENES FOR METABOLISM AND TRANSPORT BY TRANS-STILBENE OXIDE IN LIVERS OF SPRAGUE-DAWLEY AND WISTAR-KYOTO RATS Drug Metab. Dispos., July 1, 2006; 34(7): 1190 - 1197. [Abstract] [Full Text] [PDF]