Antioxidant protection by bilirubin in arsenic induced toxicity and disease

Arsenic is one of the world’s most ubiquitous environmental toxicants, with humans being exposed from air, food and water. However, elevated arsenic levels in drinking water are the major cause of toxicity, and are a health issue in many of the communities in this country that are in proximity to Superfund sites. Chronic arsenic toxicity and the health issues linked to exposure have been termed arsenicosis by the World Health Organization, with toxicity being seen from skin manifestations to liver fibrosis and cancer. A prevailing theory in arsenic toxicity is its ability to induce oxidative stress, which then initiates cellular and molecular changes leading to tissue damage. Using new animal models that show sustained elevations in serum bilirubin, a potent and natural antioxidant, experiments will be conducted in collaboration with our SRP research colleagues to examine the impact of bilirubin induced antioxidant protection on the development of arsenic induced liver fibrosis and hepatocellular carcinoma (HCC). Steady-state levels of serum bilirubin are maintained by UDP-glucuronosyltransferase 1A1 (UGT1A1) metabolism. By modifying the expression levels of UGT1A1 in humanized UGT1 mice or through conditional deletion of the liver Ugt1 locus, the steady-state levels of serum bilirubin can be reset in both neonatal and adult mice, allowing us to investigate the actions of arsenic in inducing cellular programs responsible for gene expression, fibrosis and HCC. We will characterize the cellular and molecular actions of arsenic in humanized UGT1 (hUGT1) mice where it is shown that oral arsenic intake to neonatal mice dramatically induces intestinal UGT1A1 leading to a reversal in neonatal hyperbilirubinemia. These studies will provide new molecular mechanisms on the potential oxidative actions of acute oral arsenic exposure on induction of the human UGT1A1 gene. We will utilize a new conditional knockout model of the murine Ugt1 locus showing elevated bilirubin levels when the Ugt1 locus is deleted in liver, generating Ugt1ΔHEP mice. In collaborations with Drs. Karin and Seki, antioxidant protection initiated by hUGT1 mice expressing the promoter defective UGT1A1*28 allele and Ugt1ΔHEP mice will be used in combination to examine the contribution of elevated serum bilirubin towards preventing genetically induced oxidative damage and arsenic initiated liver fibrosis and cancer. These studies will culminate in a more complete understanding of molecular and epigenetic effects of antioxidant protection on arsenic induced liver toxicity and disease.


PubMed Central ID: 

Chen, S., Lu, W., Yueh, M.-F., Rettenmeier, E., Liu, M., Auwerx, J., Yu, R.T., Evans, R.M., Wang, K., Karin, M., Tukey, R.H. (2017) Intestinal NCoR1, a newly discovered regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia.  Proc. Nat. Acad. Sci. USA.114:E1432-E1440. doi: 10.1073/pnas.1700232114.

PubMedID: 28167773
PubMed Central ID: 

Hirashima R., Itoh T., Tukey R.H., Fujiwara R. (2017) Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. doi: 10.1002/jat.3435.

PubMedID: 28138970
PubMed Central ID: 

Hirashima R., Michimae H., Takemoto H., Sasaki A., Kobayashi Y., Itoh T., Tukey R.H., Fujiwara R. (2016) Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity. Mol Pharmacol. 90:265-74. doi: 10.1124/mol.116.104174.

PubMedID: 27413119
PubMed Central ID: 

Liu M., Chen S., Yueh M.F., Fujiwara R., Konopnicki C., Hao H., Tukey R.H. (2016) Cadmium and arsenic override NF-κB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia. Biochem Pharmacol. 110-111:37-46. doi:10.1016/j.bcp.2016.04.003.

PubMedID: 27060662
PubMed Central ID: 

Touboul, T., Chen, S., To, C.C., Mora-Castilla, S., Sabatini, K., Tukey, R.H., Laurent, L.C. (2016) Stage-specific regulation of the WNT/β-catenin pathway results in improved differentiation of hESCs to functional hepatocytes. J Hepatol. 64(6):1315-26. doi: 10.1016/j.jhep.2016.02.028.

PubMedID: 26921690
PubMed Central ID: 

Liu M., Chen S., Yueh M.F., Want G., Hao H., Tukey R.H. (2016) Reduction of p53 by knockout of the UGT1 locus in colon epithelial cells causes an increase in tumorigenesis. Cellular and Molecular Gastro and Hepatology. 2:63-76. doi: 10.1016/j.jcmgh.2015.08.008.

PubMedID: 26807433
PubMed Central ID: 

Yueh M.F., Tukey R.H. (2016) Triclosan: A widespread environmental toxicant with many biological effects. Annu Rev Pharmacol Toxicol. 56: 251-72. doi: 10.1146/annurev-pharmtox-010715-103417

PubMedID: 26738475
PubMed Central ID: 

Barateiro, A., Chen, S., Yueh, M. F., Fernandes, A., Domingues, H. S., Relvas, J., Barbier, O., Nguyen, N., Tukey, R. H., Brites, D. (2016) Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia. Mol Pharmacol. 89(1):84-93. doi: 10.1124/mol.115.098228.

PubMedID: 26480925
PubMed Central ID: 

Fujiwara, R., Maruo, Y., Chen, S., Tukey, R. H. (2015) Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol Appl Pharmacol. doi: 10.1016/j.taap.2015.08.018.

PubMedID: 26342858
PubMed Central ID: 

Sakamoto, M., Itoh, T., Tukey, R. H., Fujiwara, R. (2015) Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain. Drug Metab Pharmacokinet. 30(4), 269-75. doi: 10.1016/j.dmpk.2015.04.004.

PubMedID: 26210671
PubMed Central ID: 

Landrigan, P. J., Wright, R. O., Cordero, J. F., Eaton, D. L., Goldstein, B. D., Hennig, B., Maier, R. M., Ozonoff, D. M., Smith, M. T., Tukey, R. H. (2015) The NIEHS Superfund Research Program: 25 Years of Translational Research for Public Health. Environ Health Perspect. 123(10), 909-18. doi: 10.1289/ehp.1409247.

PubMedID: 25978799
PubMed Central ID: 

Kutsuno, Y., Hirashima, R., Sakamoto, M., Ushikubo, H., Michimae, H., Itoh, T., Tukey, R. H., Fujiwara, R. (2015) Expression of UDP-Glucuronosyltransferase 1 (UGT1) and Glucuronidation Activity toward Endogenous Substances in Humanized UGT1 Mouse Brain. Drug Metab Dispos. 43(7),1071-6. doi: 10.1124/dmd.115.063719.

PubMedID: 25953521
PubMed Central ID: 

Yueh, M. F., Taniguchi, K., Chen, S., Evans, R. M., Hammock, B. D., Karin, M., Tukey, R. H. (2014) The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci USA. 111(48):17200-5. doi: 10.1073/pnas.1419119111.

PubMedID: 25404284
PubMed Central ID: 

Aoshima, N., Fujie, Y., Itoh, T., Tukey, R. H., Fujiwara, R. (2014) Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia. Sci Rep. 4:6343. doi: 10.1038/srep06343.

PubMedID: 25209391
PubMed Central ID: 

Kutsuno, Y., Itoh, T., Tukey, R. H., Fujiwara, R. (2014) Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice. Drug Metab Dispos 42(7), 1146-52. doi: 10.1124/dmd.114.057083.

PubMedID: 24764149
PubMed Central ID: 

Maruo, Y., Morioka, Y., Fujito, H., Nakahara, S., Yanagi, T., Matsui, K., Mori, A., Sato, H., Tukey, R. H., Takeuchi, Y. (2014) Bilirubin Uridine Diphosphate-Glucuronosyltransferase Variation Is a Genetic Basis of Breast Milk Jaundice. J Pediatr. doi: 10.1016/j.jpeds.2014.01.060.

PubMedID: 24650397
PubMed Central ID: 

Yueh, M. F., Chen, S., Nguyen, N., Tukey, R. H. (2014) Developmental onset of bilirubin-induced neurotoxicity involves Toll-like receptor 2-dependent signaling in humanized UDP-glucuronosyltransferase1 mice. J Biol Chem. 289(8), 4699-709. doi: 10.1074/jbc.M113.518613.

PubMedID: 24403077
PubMed Central ID: 

Chen, S., Yueh, M. F., Bigo, C., Barbier, O., Wang, K., Karin, M., Nguyen, N., Tukey, R. H. (2013) Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc Natl Acad Sci USA. 110,19143-19148. doi: 10.1073/pnas.1319123110.

PubMedID: 24191041
PubMed Central ID: 

Shibuya, A., Itoh, T., Tukey, R. H., Fujiwara, R. (2013)  Impact of fatty acids on human UDP-glucuronosyltransferase 1A1 activity and its expression in neonatal hyperbilirubinemia. Sci Rep. doi: 10.1038/srep02903.

PubMedID: 24104695
PubMed Central ID: 

Sumida, K., Kawana, M., Kouno, E., Itoh, T., Takano, S., Narawa, T., Tukey, R. H., Fujiwara, R. (2013) Importance of UDP-glucuronosyltransferase 1A1 expression in skin and its induction by UVB in neonatal hyperbilirubinemia. Mol Pharmacol. 84(5):679-86. doi: 10.1124/mol.113.088112.

PubMedID: 23950218
PubMed Central ID: 

Konopnicki, C. M., Dickmann, L. J., Tracy, J. M., Tukey, R. H., Wienkers, L. C., Foti, R. S. (2013) 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. 535(2):143-9. doi: 10.1016/

PubMedID: 23562620
PubMed Central ID: 

Li, T., Yu, R. T., Atkins, A. R., Downes, M., Tukey, R. H., Evans, R. M. (2012) Targeting the pregnane X receptor in liver injury. Expert Opin Ther Targets16(11):1075-83. doi: 10.1517/14728222.2012.715634.

PubMedID: 22913318
PubMed Central ID: 

Chen, S., Yueh, M. F., Evans, R. M., Tukey, R. H. (2012) Pregnane-x-receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 mice. Hepatology. 56(2):658-67. doi: 10.1002/hep.25671.

PubMedID: 22371261
PubMed Central ID: 

Fujiwara, R., Chen, S., Karin, M., Tukey, R.H. (2012) Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia. Gastroenterology. 142(1), 109-118. doi: 10.1053/j.gastro.2011.09.045.

PubMedID: 21983082
PubMed Central ID: 

Yueh, M. F., Mellon, P. L., Tukey, R. H. (2011) Inhibition of human UGT2B7 gene expression in transgenic mice by the constitutive androstane receptor. Mol Pharmacol. 79(6),1053-60. doi: 10.1124/mol.110.070649.

PubMedID: 21415305
PubMed Central ID: 

Fujiwara, R., Nguyen, N., Chen, S., Tukey, R. H. (2010) Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP-glucuronosyltransferase 1 (UGT1) locus. Proc Natl Acad Sci USA. 107(11), 5024-5029. doi: 10.1073/pnas.0913290107.

PubMedID: 20194756
PubMed Central ID: 

Cai, H., Nguyen, N., Peterkin, V., Young-Sun, Y., Hotz, K., Beaton-La Placa, D., Chen, S., Tukey, R. H., and Stevens, J. C. (2010) A humanized UGT1 mouse model expressing the UGT1A1*28 allele for assessing drug clearance by UGT1A1 dependent glucuronidation. Drug Metabol Dispos. 38(5), 879-86. doi: 10.1124/dmd.109.030130.

PubMedID: 20124398
PubMed Central ID: 

Argikar, U.A., Senekeo-Effenberger, K., Larson, E.E., Tukey, R.H., Remmel, R.P. (2009) Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 39(11):826-35. doi: 10.3109/00498250903188985.

PubMedID: 19845433

Nguyen, N., Bonzo, J. A., Chen, S., Chouinard, S., Kelner, M., Hardiman, G., Belanger, A., and Tukey, R. H. (2008) Disruption of the Ugt1 locus in mice resembles human Crigler-Najjar type I disease. J Biol Chem. 283(12):7901-11. doi: 10.1074/jbc.M709244200.

PubMedID: 18180294
PubMed Central ID: 

Pezzoli, K., Tukey, R., Sarabia, H., Zaslavsky, I., Miranda, M. L., Suk, W. A., Lin, A., Ellisman, M. (2007) The NIEHS Environmental Health Sciences Data Resource Portal: placing advanced technologies in service to vulnerable communities. Environ Health Perspect. 115(4), 564-71. doi: 10.1289/ehp.9817

PubMedID: 17450225

Yueh, M. F., and Tukey, R. H. (2007) Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice. J Biol Chem. 282(12):8749-58. doi: 10.1074/jbc.M610790200.

PubMedID: 17259171

Bonzo, J. A., Belanger, A., and Tukey, R. H. (2007) The role of chrysin and the Ah receptor in induction of the human UGT1A1 gene in vitro and in transgenic UGT1 mice. Hepatology. 45(2):349-60. doi: 10.1002/hep.21481.

PubMedID: 17256720

Senekeo-Effenberger, K., Chen, S., Yueh, M-F., Erace-Sinnokrak, E., Bonzo, J. A., Argikar, U., Kaeding, J., Trottier, T., Remmel, R. P., Ritter, J. K., Barbier, O., and Tukey, R. H. (2007) 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 Met Disp. 35(3):419-27. doi: 10.1124/dmd.106.013243.

PubMedID: 17151188

Operaña, T. N., Nguyen, N., Chen, S., Beaton, D. and Tukey, R. H. (2007) Human CYP1A1GFP expression in transgenic mice serves as a biomarker for environmental toxicant exposure. Toxicol Sci. 95(1):98-107. doi: 10.1093/toxsci/kfl144.

PubMedID: 17065433

Chen, S., Beaton, D., Nguyen, N., Senekeo-Effenberger, K., Brace-Sinnokrak, E., Argikar, U., Remmel, R. P., Trottier, J., Barbier, O., Ritter, J., Tukey, R. H. (2005) Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltranserase-1 (UGT1) locus. J Biol Chem. 280(45):37547-57. doi: 10.1074/jbc.M506683200.

PubMedID: 16155002

Machemer D. E. W., and Tukey R. H. (2005) The role of protein kinase C in regulation of TCDD-mediated CYP1A1 gene expression. Toxicol Sci. 87(1):27-37. doi: 10.1093/toxsci/kfi220.

PubMedID: 15947024

Bonzo, J. A., Chen, S., Galijatovic, A., Tukey, R. H. (2005) Arsenite inihibition of CYP1A1 induction by TCDD is independent of cell cycle arrest. Mol Pharmacol. 67(4):1247-56. doi: 10.1124/mol.104.006130.

PubMedID: 15630080

Chen, S., Operana, T., Bonzo, J., Nguyen, N., Tukey R. H. (2005) Erk kinase inhibition stabilizes the aryl hydrocarbon receptor. J Biol Chem. 280(6):4350-9. doi: 10.1074/jbc.M411554200.

PubMedID: 15572374

Galijatovic, A., Beaton, D., Nguyen, N., Chen, S., Bonzo, J., Johnson, R., Maeda, S., Karin, M., Guengerich, F. P., Tukey, R. H. (2004) The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice. J Biol Chem. 279(23), 23969-76. doi: 10.1074/jbc.M400973200

PubMedID: 15037607

Chen, S., Nguyen, N., Tamura, K., Karin, M., Tukey, R. H. (2003) 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. 278(21), 19526-33. doi: 10.1074/jbc.M300780200.

PubMedID: 12637498

Yueh, M. F., Huang, Y. H., Hiller, A., Chen, S., Nguyen, N., Tukey, R. H. (2003) Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. J Biol Chem. 278(17), 15001-6. doi: 10.1074/jbc.M300645200.

PubMedID: 12566446

Huang, Y. H., Galijatovic, A., Nguyen, N., Geske, D., Beaton, D., Green, J., Green, M., Peters, W. H., Tukey, R. H. (2002) Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics.12(4), 287-97.

PubMedID: 12042666

Main Contact Information

 Project Leader

  • Dr. Robert H. Tukey  

Superfund Related Project Members

  • Nghia Nguyen, Lab Manager
  • Shujuan Chen, Asst. Faculty
  • Mei-Fei Yueh, Asst. Project Scientist

Other UCSD Superfund Projects:

Administrative Core

Training Core


Dr. Robert H. Tukey, UCSD Dept. of Pharmacology

UCSD Biomedical Sciences Graduate Program

References From PubMed (NCBI)

Dr. Robert H. Tukey
University of California, San Diego
Department of Pharmacology
9500 Gilman Drive, Mail code 0722 
La Jolla, CA 92093-0722

Additional Publications

Full Publication List for Dr. Robert H. Tukey (downloadable)

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UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722