Advertisement

Involvement of the Xenobiotic Response Element (XRE) in Ah Receptor-mediated Induction of Human UDP-glucuronosyltransferase 1A1*

  • Mei-Fei Yueh
    Affiliations
    Departments of Pharmacology, Chemistry & Biochemistry, Laboratory of Environmental Toxicology, University of California San Diego, La Jolla, California 92093-0636
    Search for articles by this author
  • Yue-Hua Huang
    Affiliations
    Departments of Pharmacology, Chemistry & Biochemistry, Laboratory of Environmental Toxicology, University of California San Diego, La Jolla, California 92093-0636
    Search for articles by this author
  • Anita Hiller
    Affiliations
    Departments of Pharmacology, Chemistry & Biochemistry, Laboratory of Environmental Toxicology, University of California San Diego, La Jolla, California 92093-0636
    Search for articles by this author
  • Shujuan Chen
    Affiliations
    Departments of Pharmacology, Chemistry & Biochemistry, Laboratory of Environmental Toxicology, University of California San Diego, La Jolla, California 92093-0636
    Search for articles by this author
  • Nghia Nguyen
    Affiliations
    Departments of Pharmacology, Chemistry & Biochemistry, Laboratory of Environmental Toxicology, University of California San Diego, La Jolla, California 92093-0636
    Search for articles by this author
  • Robert H. Tukey
    Correspondence
    To whom correspondence should be addressed. Tel.: 858-822-0288; Fax: 858-822-0363
    Affiliations
    Departments of Pharmacology, Chemistry & Biochemistry, Laboratory of Environmental Toxicology, University of California San Diego, La Jolla, California 92093-0636
    Search for articles by this author
  • Author Footnotes
    * This work was supported in part by United States Public Health Service Grants GM49135 and ES10337.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:February 03, 2003DOI:https://doi.org/10.1074/jbc.M300645200
      UDP-glucuronosyltransferase 1A1 (UGT1A1) plays an important physiological role by contributing to the metabolism of endogenous substances such as bilirubin in addition to xenobiotics and drugs. The UGT1A1 gene has been shown to be inducible by nuclear receptors steroid xenobiotic receptor (SXR) and the constitutive active receptor, CAR. In this report, we show that in human hepatoma HepG2 cells the UGT1A1 gene is also inducible with aryl hydrocarbon receptor (Ah receptor) ligands such as 2,3,7,8-tetrachlodibenzo-p-dioxin (TCDD), β-naphthoflavone, and benzo[a]pyrene metabolites. Induction was monitored by increases in protein and catalytic activity as well as UGT1A1 mRNA. To examine the molecular interactions that controlUGT1A1 expression, the gene was characterized and induction by Ah receptor ligands was regionalized to bases −3338 to −3287. Nucleotide sequence analysis of this UGT1A1 enhancer region revealed a xenobiotic response element (XRE) at −3381/−3299. The dependence of the XRE on UGT1A1-luciferase activity was demonstrated by a loss of Ah receptor ligand inducibility when the XRE core region (CACGCA) was deleted or mutated. Gel mobility shift analysis confirmed that TCDD induction of nuclear proteins specifically bound to the UGT1A1-XRE, and competition experiments with Ah receptor and Arnt antibodies demonstrated that the nuclear protein was the Ah receptor. These observations reveal that the Ah receptor is involved in human UGT1A1 induction.
      UGT
      glucuronosyltransferase
      TCDD
      2,3,7,8-tetrachlodibenzo-p-dioxin
      CAR
      constitutive active receptor
      SXR
      steroid xenobiotic receptor
      BNF
      β-naphthoflavone
      B[a]P
      benzo[a]pyrene
      Tricine
      N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine
      DTT
      dithiothreitol
      XRE
      xenobiotic response element
      DRE
      drug response element
      Glucuronidation has evolved in vertebrates to catalyze the transfer of glucuronic acid from uridine 5′-diphosphoglucuronic acid to soluble non-lipid dependent substances generated as byproducts of dietary and cellular metabolism (
      • Dutton G.J.
      ). Some of the endogenous agents that are targets for glucuronidation are bilirubin and many of the steroids as well as several phenolic neurotransmitters. In addition, hundreds of drugs and xenobiotics are subject to glucuronidation (
      • Miners J.O.
      • Mackenzie P.I.
      ,
      • Tukey R.H.
      • Strassburg C.P.
      ). The vast numbers of endogenous and exogenous substances that are susceptible to glucuronidation in humans are catalyzed by the family of UDP-glucuronosyltransferases (UGTs).1 A comparison of the deduced amino acid sequence of the UGTs in mammalian species has helped in classifying these proteins as members of the UGT1 or UGT2 gene family (
      • Mackenzie P.I.
      • Owens I.S.
      • Burchell B.
      • Bock K.W.
      • Bairoch A.
      • Belanger A.
      • Fournel-Gigleux S.
      • Green M.
      • Hum D.W.
      • Iyanagi T.
      • Lancet D.
      • Louisot P.
      • Magdalou J.
      • Chowdhury
      • Ritter Jr., J.K.
      • Schachter H.
      • Tephly T.R.
      • Tipton K.F.
      • Nebert D.W.
      ). In humans, 16 cDNAs have been identified and shown through expression experiments in tissue culture to encode proteins that display functional glucuronidation activity (
      • Tukey R.H.
      • Strassburg C.P.
      ). It is generally felt that evolutionary constraints associated with the UGT1 family of proteins leads to more efficient glucuronidation of drugs and xenobiotics, whereas the UGT2 family of proteins displays far greater catalytic diversity toward endogenous agents such as steroids.
      Regulation of the UGTs in human tissues is tightly controlled. Analysis of RNA expression patterns has demonstrated that no two tissues display the same pattern of UGT gene expression, indicating that regulatory control occurs in a tissue-specific manner (
      • Tukey R.H.
      • Strassburg C.P.
      ). In addition, environmental influences on gene control clearly indicate that the UGTs are capable of undergoing differential regulation resulting in enhanced glucuronidation capacity. The treatment of Caco-2 cells with the antioxidant tert-butylhydroquinone leads to induction of UGT1A6, UGT1A9, and UGT2B7 (
      • Munzel P.A.
      • Schmohl S.
      • Heel H.
      • Kalberer K.
      • Bock-Hennig B.S.
      • Bock K.W.
      ,
      • Bock K.W.
      • Eckle T.
      • Ouzzine M.
      • Fournel-Gigleux S.
      ). Transcriptional regulation ofUGT1A6 and UGT1A9 occurs after exposure to Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (
      • Munzel P.A.
      • Schmohl S.
      • Heel H.
      • Kalberer K.
      • Bock-Hennig B.S.
      • Bock K.W.
      ,
      • Munzel P.A.
      • Lehmkoster T.
      • Bruck M.
      • Ritter J.K.
      • Bock K.W.
      ). Human UGT1A1 has recently been shown to be under control by agents that induce gene expression in concordance with the constitutive active receptor (CAR) (
      • Sugatani J.
      • Kojima H.
      • Ueda A.
      • Kakizaki S.
      • Yoshinari K.
      • Gong Q.H.
      • Owens I.S.
      • Negishi M.
      • Sueyoshi T.
      ) and the steroid xenobiotic receptor (SXR) (
      • Xie W.
      • Yeuh M.-F.
      • Radominska-Pandya A.
      • Saini S.P.S.
      • Negishi Y.
      • Bottroff B.S.
      • Cabrera G.Y.
      • Tukey R.H.
      • Evan R.M.
      ). The treatment of HepG2 and Caco-2 cells with the flavonoid chrysin leads to the induction of UGT1A1 (
      • Walle T.
      • Otake Y.
      • Galijatovic A.
      • Ritter J.K.
      • Walle U.K.
      ,
      • Galijatovic A.
      • Otake Y.
      • Walle U.K.
      • Walle T.
      ,
      • Galijatovic A.
      • Walle U.K.
      • Walle T.
      ). Interestingly, flavonoids have also been shown to induceCYP1A1 (
      • Allen S.W.
      • Mueller L.
      • Williams S.N.
      • Quattrochi L.C.
      • Raucy J.
      ) in a CYP1A1-luciferase reporter HepG2 cell line (
      • Postlind H.
      • Vu T.P.
      • Tukey R.H.
      • Quattrochi L.C.
      ), implicating a potential role for the induction ofUGT1A1 through a similar mechanism. One potential mechanism that may link the expression of UGT1A1 and CYP1A1by flavonoids is the ability of these agents to activate the Ah receptor. Although the mechanisms surrounding expression ofCYP1A1 after activation of the Ah receptor are well documented (
      • Gu Y.Z.
      • Hogenesch J.B.
      • Bradfield C.A.
      ,
      • Denison M.S.
      • Whitlock Jr., J.P.
      ,
      • Whitlock J.P.J.
      • Chichester C.H.
      • Bedgood R.M.
      • Okino S.T.
      • Ko H.P.
      • Ma Q.
      • Dong L.
      • Li H.
      • Clarke-Katzenberg R.
      ), there is little information linking expression of the human UGT1A1 gene through an Ah receptor-dependent mechanism. Experiments were undertaken in this study to examine the actions of several Ah receptor ligands to modulate expression of the UGT1A1 gene.

      DISCUSSION

      The human UGT1A1 gene plays an important role in normal physiology by serving as the only source for the glucuronidation of bilirubin (
      • Bosma P.J.
      • Seppen J.
      • Goldhoorn B.
      • Bakker C.
      • Oude E.R.
      • Chowdhury J.R.
      • Chowdhury N.R.
      • Jansen P.L.
      ), the byproduct of heme degradation. The gene is expressed differentially in a tissue-specific fashion in humans (
      • Strassburg C.P.
      • Nguyen N.
      • Manns M.P.
      • Tukey R.H.
      ,
      • Strassburg C.P.
      • Strassburg A.
      • Nguyen N.
      • Li Q.
      • Manns M.P.
      • Tukey R.H.
      ,
      • Strassburg C.P.
      • Kneip S.
      • Topp J.
      • Obermayer-Straub P.
      • Barut A.
      • Tukey R.H.
      • Manns M.P.
      ), indicating that multiple regulatory factors are involved inUGT1A1 expression. Several recent findings confirm thatUGT1A1 can also be regulated by environmental exposure. Exposure of HepG2 (
      • Walle T.
      • Otake Y.
      • Galijatovic A.
      • Ritter J.K.
      • Walle U.K.
      ) and Caco-2 Cells (
      • Galijatovic A.
      • Otake Y.
      • Walle U.K.
      • Walle T.
      ) by specific bioflavonoids (
      • Walle T.
      • Otake Y.
      • Galijatovic A.
      • Ritter J.K.
      • Walle U.K.
      ,
      • Walle U.K.
      • Walle T.
      ) induces UGT1A1. In primary human hepatocytes, treatment with phenobarbital, oltipraz, and 3-methylcholanthrene led to the induction of UGT1A1 mRNA and protein (
      • Ritter J.K.
      • Kessler F.K.
      • Thompson M.T.
      • Grove A.D.
      • Auyeung D.J.
      • Fisher R.A.
      ). The phenobarbital-type inducer TCPOBOP activates the human UGT1A1 gene through CAR at a nuclear receptor sequence (NR1) between bases −3483/−3194. Work in our laboratory has recently identified a human SXR binding site in this same region (
      • Xie W.
      • Yeuh M.-F.
      • Radominska-Pandya A.
      • Saini S.P.S.
      • Negishi Y.
      • Bottroff B.S.
      • Cabrera G.Y.
      • Tukey R.H.
      • Evan R.M.
      ). These results demonstrate that theUGT1A1 gene undergoes differential regulation because of tissue-specific expression and inducibility with drugs and xenobiotics. In addition to these responses, we have demonstrated that theUGT1A1 gene is also regulated by the human Ah receptor in response to TCDD, BNF, and B[a]P metabolites.
      HepG2 cells exposed to TCDD and BNF induces UGT1A1, as shown by Western blot analysis and indirectly by an increase in 17α-ethynylestradiol UGT activity. The Ah receptor is functional in these cells as evident from the induction of CYP1A1 protein as well as regulation of aCYP1A1-luciferase promoter. We have mapped a regulatory sequence on the UGT1A1 gene that contains an XRE core sequence, which is positioned in close proximity to the NR1 (
      • Sugatani J.
      • Kojima H.
      • Ueda A.
      • Kakizaki S.
      • Yoshinari K.
      • Gong Q.H.
      • Owens I.S.
      • Negishi M.
      • Sueyoshi T.
      ) and SXR binding sites (Fig. 5B). An oligonucleotide encoding bases −3318/−3294 containing the Ah receptor binding sequence CACGCA associates with the activated nuclear Ah receptor in HepG2 cells. Mutation of this sequence eliminates binding of the Ah receptor, whereas the generation of enhancer constructs containing the same mutation leads to a loss of TCDD and BNF induction of transfected reporter gene activity. It would appear that this single responsive element plays an important role in regulation of UGT1A1after exposure to TCDD and BNF.
      The identification of the UGT1A1-XRE suggests that Ah receptor ligands may regulate UGT1A1 in a fashion comparable with CYP1A1. Along with results that we have presented for TCDD and BNF, other polycyclic aromatic hydrocarbons such as metabolites of B[a]P are capable of inducing UGT1A1. In addition, there is building evidence that some of the flavonoids modulate gene regulation in part through the Ah receptor. Chrysin is a potent inducer of UGT1A1 (
      • Walle T.
      • Otake Y.
      • Galijatovic A.
      • Ritter J.K.
      • Walle U.K.
      ) and is able to induce the expression ofCYP1A1, as demonstrated through induction ofCYP1A1-luciferase in TV101 cells.
      A. Galijatovic and R. H. Tukey, unpublished results.
      Studies in rats show that Ah receptor ligands such as 3-methylcholanthrene are capable of inducing intestinal Ugt1a1 (
      • Grams B.
      • Harms A.
      • Braun S.
      • Strassburg C.P.
      • Manns M.P.
      • Obermayer-Straub P.
      ), and it is well known that 3-methylcholanthene is a potent Ah receptor ligand. Omeprazole, a benzimidazole used in the treatment of peptic ulcer disease, activates the Ah receptor and induces CYP1A1 (
      • Quattrochi L.C.
      • Tukey R.H.
      ). Although not directly demonstrating induction of UGT1A1, omeprazole therapy has been shown to increase duodenal 3-hydroxybenzo[a]pyrene UGT activity greater than 5-fold (
      • Kashfi K.
      • McDougall C.J.
      • Dannenberg A.J.
      ). UGT1A1 is abundantly expressed in the small intestine (
      • Strassburg C.P.
      • Kneip S.
      • Topp J.
      • Obermayer-Straub P.
      • Barut A.
      • Tukey R.H.
      • Manns M.P.
      ). However, it is important to appreciate that dual regulation of UGT1A1 and CYP1A1 may not always occur. Apigenin, a flavonoid that is a potent inducer of human UGT1A1 (
      • Walle U.K.
      • Walle T.
      ), has very limited capacity to induce CYP1A1, as measured by induction of CYP1A1-luciferase in TV101 cells (
      • Allen S.W.
      • Mueller L.
      • Williams S.N.
      • Quattrochi L.C.
      • Raucy J.
      ). Apigenin may regulate UGT1A1 in a manner that is independent of the Ah receptor.
      As described by Sugatani et al. (
      • Sugatani J.
      • Kojima H.
      • Ueda A.
      • Kakizaki S.
      • Yoshinari K.
      • Gong Q.H.
      • Owens I.S.
      • Negishi M.
      • Sueyoshi T.
      ) and expanded by these studies and others (
      • Xie W.
      • Yeuh M.-F.
      • Radominska-Pandya A.
      • Saini S.P.S.
      • Negishi Y.
      • Bottroff B.S.
      • Cabrera G.Y.
      • Tukey R.H.
      • Evan R.M.
      ), the UGT1A1 gene can be regulated by ligands that activate nuclear receptors CAR, SXR, and the Ah receptor. These cis-acting regulatory elements are positioned within a 125-base pair region on the UGT1A1 gene between bases −3424 and −3299. The location of these xenobiotic receptors in close proximity to each other may serve an important biological role in maintaining adequate expression levels UGT1A1. SXR and CAR are part of the orphan nuclear receptors that are structurally related to nuclear hormone receptors. It has been proposed that the xenobiotic nuclear receptors compose a family of regulatory proteins that are involved in steroid and xenobiotic sensing, leading to altered gene expression patterns essential for normal homeostasis (
      • Blumberg B.
      • Sabbagh Jr., W.
      • Juguilon H.
      • Bolado Jr., J.
      • van Meter C.M.
      • Ong E.S.
      • Evans R.M.
      ,
      • Jones S.A.
      • Moore L.B.
      • Shenk J.L.
      • Wisely G.B.
      • Hamilton G.A.
      • McKee D.D.
      • Tomkinson N.C.
      • LeCluyse E.L.
      • Lambert M.H.
      • Willson T.M.
      • Kliewer S.A.
      • Moore J.T.
      ). Originally postulated to regulate CYP3A genes, these nuclear receptors are now known to regulate a number of phase I and phase II xenobiotic enzymes. Although not part of the nuclear receptor family, the Ah receptor also serves to modulate phase I and phase II enzymes in response to environmental stimuli. Thus, regulation ofUGT1A1 can be controlled by numerous endogenous agents that are ligands for SXR and CAR as well as xenobiotics that are ligands for SXR, CAR, and the Ah receptor.

      Acknowledgments

      We thank Dr. Joe Ritter, Department of Pharmacology and Toxicology, Virginia Commonwealth University, for a sample of the anti-UGT1A1 antibody and Dr. Fred Guengerich, Department of Biochemistry, Vanderbilt University, for a sample of the anti-CYP1A1 antibody. Dr. Christopher Bradfield, McArdle Laboratory for Cancer Research, University of Wisconsin, provided aliquots of the anti-Ah receptor and anti-Arnt antibodies, and Dr. Wilbert H. Peters, Department of Gastroenterology, St. Radbound University Hospital, Njimegen, The Netherlands, provided a sample of the anti-UGT antibody.

      References

        • Dutton G.J.
        Glucuronidation of Drugs and Other Compounds. CRC Press, Inc., Boca Raton, FL1980
        • Miners J.O.
        • Mackenzie P.I.
        Pharmacol. Ther. 1991; 51: 347-369
        • Tukey R.H.
        • Strassburg C.P.
        Annu. Rev. Pharmacol. Toxicol. 2000; 40: 581-616
        • Mackenzie P.I.
        • Owens I.S.
        • Burchell B.
        • Bock K.W.
        • Bairoch A.
        • Belanger A.
        • Fournel-Gigleux S.
        • Green M.
        • Hum D.W.
        • Iyanagi T.
        • Lancet D.
        • Louisot P.
        • Magdalou J.
        • Chowdhury
        • Ritter Jr., J.K.
        • Schachter H.
        • Tephly T.R.
        • Tipton K.F.
        • Nebert D.W.
        Pharmacogenetics. 1997; 7: 255-269
        • Tukey R.H.
        • Strassburg C.P.
        Mol. Pharmacol. 2001; 59: 405-414
        • Munzel P.A.
        • Schmohl S.
        • Heel H.
        • Kalberer K.
        • Bock-Hennig B.S.
        • Bock K.W.
        Drug Metab. Dispos. 1999; 27: 569-573
        • Bock K.W.
        • Eckle T.
        • Ouzzine M.
        • Fournel-Gigleux S.
        Biochem. Pharmacol. 2000; 59: 467-470
        • Munzel P.A.
        • Lehmkoster T.
        • Bruck M.
        • Ritter J.K.
        • Bock K.W.
        Arch. Biochem. Biophys. 1998; 350: 72-78
        • Sugatani J.
        • Kojima H.
        • Ueda A.
        • Kakizaki S.
        • Yoshinari K.
        • Gong Q.H.
        • Owens I.S.
        • Negishi M.
        • Sueyoshi T.
        Hepatology. 2001; 33: 1232-1238
        • Walle T.
        • Otake Y.
        • Galijatovic A.
        • Ritter J.K.
        • Walle U.K.
        Drug Metab. Dispos. 2000; 28: 1077-1082
        • Galijatovic A.
        • Otake Y.
        • Walle U.K.
        • Walle T.
        Pharmacol. Res. 2001; 18: 374-379
        • Galijatovic A.
        • Walle U.K.
        • Walle T.
        Pharmacol. Res. 2000; 17: 21-26
        • Allen S.W.
        • Mueller L.
        • Williams S.N.
        • Quattrochi L.C.
        • Raucy J.
        Drug Metab. Dispos. 2001; 29: 1074-1079
        • Postlind H.
        • Vu T.P.
        • Tukey R.H.
        • Quattrochi L.C.
        Toxicol. Appl. Pharmacol. 1993; 118: 255-262
        • Gu Y.Z.
        • Hogenesch J.B.
        • Bradfield C.A.
        Annu. Rev. Pharmacol. Toxicol. 2000; 40: 519-561
        • Denison M.S.
        • Whitlock Jr., J.P.
        J. Biol. Chem. 1995; 270: 18175-18178
        • Whitlock J.P.J.
        • Chichester C.H.
        • Bedgood R.M.
        • Okino S.T.
        • Ko H.P.
        • Ma Q.
        • Dong L.
        • Li H.
        • Clarke-Katzenberg R.
        Drug Metab. Rev. 1997; 29: 1107-1127
        • Bansal S.K.
        • Gessner T.
        Anal. Biochem. 1980; 109: 321-329
        • Ritter J.K.
        • Kessler F.K.
        • Thompson M.T.
        • Grove A.D.
        • Auyeung D.J.
        • Fisher R.A.
        Hepatology. 1999; 30: 476-484
        • Soucek P.
        • Martin M.V.
        • Ueng Y.F.
        • Guengerich F.P.
        Biochemistry. 1995; 34: 16013-16021
        • Gong Q.H.
        • Cho J.W.
        • Huang T.
        • Potter C.
        • Gholami N.
        • Basu N.K.
        • Kubota S.
        • Carvalho S.
        • Pennington M.W.
        • Owens I.S.
        • Popescu N.C.
        Pharmacogenetics. 2001; 11: 357-368
        • Chen Y.-H.
        • Tukey R.H.
        J. Biol. Chem. 1996; 271: 26261-26266
        • Quattrochi L.C.
        • Tukey R.H.
        Mol. Pharmacol. 1993; 43: 504-508
        • Merchant M.
        • Wang X.
        • Kamps C.
        • Rosengren R.
        • Morrison V.
        • Safe S.
        Arch. Biochem. Biophys. 1992; 292: 250-257
        • Anderson J.W.
        • Jones J.
        • Steinert S.
        • Sanders B.
        • Means J.
        • McMillin D.
        • Vu T.
        • Tukey R.H.
        Marine Environ. Res. 1999; 48: 389-405
        • Ziccardi M.H.
        • Gardner I.A.
        • Denison M.S.
        Environ. Toxicol. Chem. 2002; 21: 2027-2033
        • Peters W.H.
        • Allebes W.A.
        • Jansen P.L.
        • Poels L.G.
        • Capel P.J.
        Gastroenterology. 1987; 93: 162-169
        • Bosma P.J.
        • Seppen J.
        • Goldhoorn B.
        • Bakker C.
        • Oude E.R.
        • Chowdhury J.R.
        • Chowdhury N.R.
        • Jansen P.L.
        J. Biol. Chem. 1994; 269: 17960-17964
        • Strassburg C.P.
        • Nguyen N.
        • Manns M.P.
        • Tukey R.H.
        Mol. Pharmacol. 1998; 54: 647-654
        • Strassburg C.P.
        • Strassburg A.
        • Nguyen N.
        • Li Q.
        • Manns M.P.
        • Tukey R.H.
        Biochem. J. 1999; 338: 489-498
        • Strassburg C.P.
        • Kneip S.
        • Topp J.
        • Obermayer-Straub P.
        • Barut A.
        • Tukey R.H.
        • Manns M.P.
        J. Biol. Chem. 2000; 46: 36164-36171
        • Walle U.K.
        • Walle T.
        Drug Metab. Dispos. 2002; 30: 564-569
        • Xie W.
        • Yeuh M.-F.
        • Radominska-Pandya A.
        • Saini S.P.S.
        • Negishi Y.
        • Bottroff B.S.
        • Cabrera G.Y.
        • Tukey R.H.
        • Evan R.M.
        Proc. Natl. Acad. Sci. U. S. A. 2003; (in press)
        • Grams B.
        • Harms A.
        • Braun S.
        • Strassburg C.P.
        • Manns M.P.
        • Obermayer-Straub P.
        Arch. Biochem. Biophys. 2000; 377: 255-265
        • Kashfi K.
        • McDougall C.J.
        • Dannenberg A.J.
        Clin. Pharmacol. Ther. 1995; 58: 625-630
        • Blumberg B.
        • Sabbagh Jr., W.
        • Juguilon H.
        • Bolado Jr., J.
        • van Meter C.M.
        • Ong E.S.
        • Evans R.M.
        Genes Dev. 1998; 12: 3195-3205
        • Jones S.A.
        • Moore L.B.
        • Shenk J.L.
        • Wisely G.B.
        • Hamilton G.A.
        • McKee D.D.
        • Tomkinson N.C.
        • LeCluyse E.L.
        • Lambert M.H.
        • Willson T.M.
        • Kliewer S.A.
        • Moore J.T.
        Mol. Endocrinol. 2000; 14: 27-39
        • Ritter J.K.
        • Chen F.
        • Sheen Y.Y.
        • Tran H.M.
        • Kimura S.
        • Yeatman M.T.
        • Owens I.S.
        J. Biol. Chem. 1992; 267: 3257-3261