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    Robert Tukey

    TitleProfessor
    SchoolUniversity of California, San Diego
    DepartmentPharmacology
    Address9500 Gilman Drive #0722
    CA La Jolla 92093
    Phone858-822-0288
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      Collapse Biography 
      Collapse Education and Training
      Ph.D.University of Iowa
      B.S.University of Minnesota

      Collapse Overview 
      Collapse Overview
      As a large branch of drug-processing genes that compose several supergene families, UDP-glucuronosyltransferase (UGT) genes possess divergent regulatory properties that can be attributed to inherited genetic variations, developmental stages, transcription factors, co-factors, repressors, or environmental stimuli. Each component of this regulatory network plays an important role in controlling functional properties of these genes, thus affecting the body's ability to glucuronidate and eliminate drugs and endogenous and environmental toxicants. By applying mouse genetic techniques to generate mice humanized with the UGT1 locus, we model complex signaling and gene regulatory events that ultimately determine the delicate balance between homeostasis and disease.

      Our current projects are as follows:
      - We discovered that UGT1A is indispensable to maintain and sustain p53 activation in stress-induced colon epithelial cells, thus impacting p53-mediated apoptosis and colon tumor suppression; further work is designed to uncover the molecular mechanism underlying UGT1A-directed modulation of cytoplasmic p53 levels.
      - By applying functional genomic approaches and employing chromatin pull-down and deep sequencing (CHIP-seq) and RNA-sequencing, we are studying the importance of the recruitment of the nuclear receptor co-repressor I (NCOR1) and resulting histone-modification dynamics on controlling the suppression of UGT1A expression.
      - We are creating novel animal models in the humanized UGT1 background to examine the effect of clinically relevant genetic variants of the UGT1A1 gene on the onset of hyperbilirubinemia and bilirubin-induced neurological dysfunction owing to the fact that UGT1A1 is the sole bilirubin-metabolizing enzyme.
      - Part of our research focus is to understand how environmental toxicants exert their adverse effects on health. We have recently demonstrated that the antibacterial agent triclosan is a liver tumor promoter. Experiments are underway to investigate how the involvement of inflammatory cytokines and what relevant oncogenic pathways contribute to TCS-induced tumorigenesis.

      Collapse Interests
      Signal Transduction, Gene Regulation, Carcinogenesis

      Collapse ORNG Applications 
      Collapse Websites
      Collapse NIH Awarded Grants

      Collapse Bibliographic 
      Collapse Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
      List All   |   Timeline
      1. Liu M, Chen S, Yueh MF, Fujiwara R, Konopnicki C, Hao H, Tukey RH. Cadmium and arsenic override NF-?B developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia. Biochem Pharmacol. 2016 Jun 15; 110-111:37-46. PMID: 27060662.
        View in: PubMed
      2. Touboul T, Chen S, To CC, Mora-Castilla S, Sabatini K, Tukey RH, Laurent LC. Stage-specific regulation of the WNT/ß-catenin pathway enhances differentiation of hESCs into hepatocytes. J Hepatol. 2016 Jun; 64(6):1315-26. PMID: 26921690.
        View in: PubMed
      3. Yueh MF, Tukey RH. Triclosan: A Widespread Environmental Toxicant with Many Biological Effects. Annu Rev Pharmacol Toxicol. 2016 Jan 6; 56:251-72. PMID: 26738475.
        View in: PubMed
      4. Barateiro A, Chen S, Yueh MF, Fernandes A, Domingues HS, Relvas J, Barbier O, Nguyen N, Tukey RH, Brites D. Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia. Mol Pharmacol. 2016 Jan; 89(1):84-93. PMID: 26480925.
        View in: PubMed
      5. Kutsuno Y, Hirashima R, Sakamoto M, Ushikubo H, Michimae H, Itoh T, Tukey RH, Fujiwara R. Expression of UDP-Glucuronosyltransferase 1 (UGT1) and Glucuronidation Activity toward Endogenous Substances in Humanized UGT1 Mouse Brain. Drug Metab Dispos. 2015 Jul; 43(7):1071-6. PMID: 25953521.
        View in: PubMed
      6. Yueh MF, Taniguchi K, Chen S, Evans RM, Hammock BD, Karin M, Tukey RH. The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci U S A. 2014 Dec 2; 111(48):17200-5. PMID: 25404284.
        View in: PubMed
      7. Kutsuno Y, Itoh T, Tukey RH, Fujiwara R. Glucuronidation of Drugs and Drug-Induced Toxicity in Humanized UDP-Glucuronosyltransferase 1 Mice. Drug Metab Dispos. 2014 Jul; 42(7):1146-52. PMID: 24764149.
        View in: PubMed
      8. Yueh MF, Chen S, Nguyen N, Tukey RH. Developmental Onset of Bilirubin-induced Neurotoxicity Involves Toll-like Receptor 2-dependent Signaling in Humanized UDP-glucuronosyltransferase1 Mice. J Biol Chem. 2014 Feb 21; 289(8):4699-709. PMID: 24403077.
        View in: PubMed
      9. Chen S, Yueh MF, Bigo C, Barbier O, Wang K, Karin M, Nguyen N, Tukey RH. Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc Natl Acad Sci U S A. 2013 Nov 19; 110(47):19143-8. PMID: 24191041.
        View in: PubMed
      10. Sumida K, Kawana M, Kouno E, Itoh T, Takano S, Narawa T, Tukey RH, Fujiwara R. Importance of UDP-glucuronosyltransferase 1A1 expression in skin and its induction by UVB in neonatal hyperbilirubinemia. Mol Pharmacol. 2013 Nov; 84(5):679-86. PMID: 23950218.
        View in: PubMed
      11. Konopnicki CM, Dickmann LJ, Tracy JM, Tukey RH, Wienkers LC, Foti RS. Evaluation of UGT protein interactions in human hepatocytes: effect of siRNA down regulation of UGT1A9 and UGT2B7 on propofol glucuronidation in human hepatocytes. Arch Biochem Biophys. 2013 Jul 15; 535(2):143-9. PMID: 23562620.
        View in: PubMed
      12. Yueh MF, Li T, Evans RM, Hammock B, Tukey RH. Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha. PLoS One. 2012; 7(6):e37705. PMID: 22761658.
        View in: PubMed
      13. Chen S, Yueh MF, Evans RM, Tukey RH. Pregnane-x-receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 mice. Hepatology. 2012 Aug; 56(2):658-67. PMID: 22371261.
        View in: PubMed
      14. Fujiwara R, Chen S, Karin M, Tukey RH. Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-?B leads to hyperbilirubinemia. Gastroenterology. 2012 Jan; 142(1):109-118.e2. PMID: 21983082.
        View in: PubMed
      15. Vogel A, Ockenga J, Tukey RH, Manns MP, Strassburg CP. Genotyping of the UDP-glucuronosyltransferase (UGT) 1A7 gene revisited. Gastroenterology. 2011 May; 140(5):1692-3. PMID: 21440586.
        View in: PubMed
      16. Fujiwara R, Nguyen N, Chen S, Tukey RH. Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus. Proc Natl Acad Sci U S A. 2010 Mar 16; 107(11):5024-9. PMID: 20194756.
        View in: PubMed
      17. Savas U, Machemer DE, Hsu MH, Gaynor P, Lasker JM, Tukey RH, Johnson EF. Opposing roles of peroxisome proliferator-activated receptor alpha and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model. J Biol Chem. 2009 Jun 12; 284(24):16541-52. PMID: 19366684.
        View in: PubMed
      18. Chouinard S, Yueh MF, Tukey RH, Giton F, Fiet J, Pelletier G, Barbier O, Bélanger A. Inactivation by UDP-glucuronosyltransferase enzymes: the end of androgen signaling. J Steroid Biochem Mol Biol. 2008 Apr; 109(3-5):247-53. PMID: 18467088.
        View in: PubMed
      19. Nguyen N, Bonzo JA, Chen S, Chouinard S, Kelner MJ, Hardiman G, Bélanger A, Tukey RH. Disruption of the ugt1 locus in mice resembles human Crigler-Najjar type I disease. J Biol Chem. 2008 Mar 21; 283(12):7901-11. PMID: 18180294.
        View in: PubMed
      20. Bonzo JA, Bélanger A, Tukey RH. The role of chrysin and the ah receptor in induction of the human UGT1A1 gene in vitro and in transgenic UGT1 mice. Hepatology. 2007 Feb; 45(2):349-60. PMID: 17256720.
        View in: PubMed
      21. Yueh MF, Tukey RH. Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice. J Biol Chem. 2007 Mar 23; 282(12):8749-58. PMID: 17259171.
        View in: PubMed
      22. Pezzoli K, Tukey R, Sarabia H, Zaslavsky I, Miranda ML, Suk WA, Lin A, Ellisman M. The NIEHS Environmental Health Sciences Data Resource Portal: placing advanced technologies in service to vulnerable communities. Environ Health Perspect. 2007 Apr; 115(4):564-71. PMID: 17450225.
        View in: PubMed
      23. Operaña TN, Tukey RH. Oligomerization of the UDP-glucuronosyltransferase 1A proteins: homo- and heterodimerization analysis by fluorescence resonance energy transfer and co-immunoprecipitation. J Biol Chem. 2007 Feb 16; 282(7):4821-9. PMID: 17179145.
        View in: PubMed
      24. Senekeo-Effenberger K, Chen S, Brace-Sinnokrak E, Bonzo JA, Yueh MF, Argikar U, Kaeding J, Trottier J, Remmel RP, Ritter JK, Barbier O, Tukey RH. Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation. Drug Metab Dispos. 2007 Mar; 35(3):419-27. PMID: 17151188.
        View in: PubMed
      25. Operaña TN, Nguyen N, Chen S, Beaton D, Tukey RH. Human CYP1A1GFP expression in transgenic mice serves as a biomarker for environmental toxicant exposure. Toxicol Sci. 2007 Jan; 95(1):98-107. PMID: 17065433.
        View in: PubMed
      26. Chen S, Beaton D, Nguyen N, Senekeo-Effenberger K, Brace-Sinnokrak E, Argikar U, Remmel RP, Trottier J, Barbier O, Ritter JK, Tukey RH. Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. J Biol Chem. 2005 Nov 11; 280(45):37547-57. PMID: 16155002.
        View in: PubMed
      27. Machemer DE, Tukey RH. The role of protein kinase C in regulation of TCDD-mediated CYP1A1 gene expression. Toxicol Sci. 2005 Sep; 87(1):27-37. PMID: 15947024.
        View in: PubMed
      28. Bonzo JA, Chen S, Galijatovic A, Tukey RH. Arsenite inhibition of CYP1A1 induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin is independent of cell cycle arrest. Mol Pharmacol. 2005 Apr; 67(4):1247-56. PMID: 15630080.
        View in: PubMed
      29. Yueh MF, Bonzo JA, Tukey RH. The role of Ah receptor in induction of human UDP-glucuronosyltransferase 1A1. Methods Enzymol. 2005; 400:75-91. PMID: 16399344.
        View in: PubMed
      30. Chen S, Operaña T, Bonzo J, Nguyen N, Tukey RH. ERK kinase inhibition stabilizes the aryl hydrocarbon receptor: implications for transcriptional activation and protein degradation. J Biol Chem. 2005 Feb 11; 280(6):4350-9. PMID: 15572374.
        View in: PubMed
      31. Galijatovic A, Beaton D, Nguyen N, Chen S, Bonzo J, Johnson R, Maeda S, Karin M, Guengerich FP, Tukey RH. The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice. J Biol Chem. 2004 Jun 4; 279(23):23969-76. PMID: 15037607.
        View in: PubMed
      32. Chen S, Nguyen N, Tamura K, Karin M, Tukey RH. The role of the Ah receptor and p38 in benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis. J Biol Chem. 2003 May 23; 278(21):19526-33. PMID: 12637498.
        View in: PubMed
      33. Yueh MF, Huang YH, Hiller A, Chen S, Nguyen N, Tukey RH. Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. J Biol Chem. 2003 Apr 25; 278(17):15001-6. PMID: 12566446.
        View in: PubMed
      34. Tukey RH, Strassburg CP, Mackenzie PI. Pharmacogenomics of human UDP-glucuronosyltransferases and irinotecan toxicity. Mol Pharmacol. 2002 Sep; 62(3):446-50. PMID: 12181419.
        View in: PubMed
      35. Huang YH, Galijatovic A, Nguyen N, Geske D, Beaton D, Green J, Green M, Peters WH, Tukey RH. Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics. 2002 Jun; 12(4):287-97. PMID: 12042666.
        View in: PubMed
      36. Strassburg A, Strassburg CP, Manns MP, Tukey RH. Differential gene expression of NAD(P)H:quinone oxidoreductase and NRH:quinone oxidoreductase in human hepatocellular and biliary tissue. Mol Pharmacol. 2002 Feb; 61(2):320-5. PMID: 11809856.
        View in: PubMed
      37. Tukey RH, Strassburg CP. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. Mol Pharmacol. 2001 Mar; 59(3):405-14. PMID: 11179432.
        View in: PubMed
      38. Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000; 40:581-616. PMID: 10836148.
        View in: PubMed
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