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.
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. pii: S0168-8278(16)00162-8. doi: 10.1016/j.jhep.2016.02.028.
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. 84-93. doi: 10.1124/mol.115.098228.
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.
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.
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.
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.
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.
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, 679-686.
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.
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 Targets. 16(11), 1075-83.
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.
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. 7901-7911.
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.
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, 8749-8758.
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, 349-360.
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, 419-427.
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, 98-107.
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, 37547-37557.
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, 27-37.
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, 1247-1256.
Chen, S., Operana, T., Bonzo, J., Nguyen, N., Tukey R. H. (2005) Erk kinase inhibition stabilizes the aryl hydrocarbon receptor. J Biol Chem. 280, 4350-4359.
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.
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.
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.
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.
Main Contact Information
- Dr. Robert H. Tukey
Superfund Related Project Members
- Alissa Lara, Administrator
- Nghia Nguyen, Lab Manager
- Shujuan Chen, Asst. Faculty
- Mei-Fei Yueh, Asst. Project Scientist
Other UCSD Superfund Projects:
Full Publication List for Dr. Robert H. Tukey (downloadable)
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UCSD Superfund Research Center
University of California, San Diego
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722