Molecular and Microbial Mechanisms Leading to Triclosan Induced Liver Fibrosis
Triclosan (TCS) is a synthetic antimicrobial agent that has been widely used in the U.S. and globally for more than 40 years. First invented in the early 1970s to be employed as an antiseptic and disinfectant in healthcare environments, TCS now comes into direct contact with humans in household settings through a large number of consumer products ranging from personal care products to food packaging materials. Consequently, its rising environmental release causes serious contamination in the environment, and it is now known as an Emerging Contaminant (EC) - a detectable but currently unregulated and frequently untreated environmental contaminant. While there have been numerous health concerns associated with TCS, our recent findings provide compelling evidence that long-term TCS exposure promotes liver carcinogenesis in mice. Using a carcinogen-induced animal model, we demonstrate that TCS causes toxicant-associated steatohepatitis (TASH) manifested by hepatic steatosis, inflammatory cell infiltration, and liver fibrosis, resulting in enhanced hepatocellular carcinoma (HCC). Similar to TCS, obesity and metabolic syndrome are also major etiologic factors causing steatohepatitis, termed nonalcoholic steatohepatitis (NASH). The rising prevalence of TASH and NASH – mirroring the increase in environmental toxicant exposure and obesity – is tightly linked to a growing epidemic of advanced liver disease. Recent animal studies have revealed that the disrupted gut microbiota (dysbiosis) plays a causative role in the pathogenesis of TASH and NASH, and patients with several types of chronic liver diseases show impairment of the gut microflora and intestinal barrier, highlighting a primary etiologic role of intestinal dysbiosis in liver disease. To explore the pathogenic mechanism underlying TCS-induced TASH, we hypothesize that “persistent TCS exposure causes a structurally disrupted intestinal microbiota that is a driving force of TASH development, and chronic overnutrition by a high-fat diet (HFD) is synergistic with TCS-induced TASH, leading to end-stage liver disease and HCC.” We propose to examine the following aims: 1) We will identify the gut microbiota composition following long-term TCS exposure using 16S rRNA sequencing and metatranscriptomics. We will also employ germ-free (GF) and humanized NASH mice to determine the role of gut flora in TCS-induced liver disease. 2) We will investigate regulatory roles of toll-like receptor (TLR) signaling in intestinal permeability and tight junctions responding to TCS treatment. We have rationalized that, reacting to TCS toxic insult, gut microbes releasing bacterial products and metabolites activate TLR signaling and initiate innate immune responses, stimulating profibrogenic and proinflammatory events in the liver. These experiments will use Myd88 liver conditional knockout mice to compare TCS and CCl4-induced liver toxicity. 3) We will evaluate whether TCS combined with a HFD confers greater susceptibility to the progression of TASH into tumorigenesis by using a diabetes animal model that displays signs of NASH following a HFD feeding. We postulate that autophagy status and IL-17A signaling underlines enhanced induction of HCC by TCS together with HFD.
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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.
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Mitsugi R., Sumida K., Fujie Y., Tukey R.H., Itoh T., Fujiwara R. Acyl-glucuronide as a Possible Cause of Trovafloxacin-Induced Liver Toxicity: Induction of Chemokine (C-X-C Motif) Ligand 2 by Trovafloxacin Acyl-glucuronide. (2016) Biol Pharm Bull. 39(10):1604-1610. doi: 10.1248/bpb.b16-00195.
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.
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.
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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.
Yueh, M. F., Tukey, R. H. (2016) Triclosan: A Widespread Environmental Toxicant with Many Biological Effects. (2016) Annu Rev Pharmacol Toxicol. 56, 251-72. doi: 10.1146/annurev-pharmtox-010715-103417.
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.
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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 (Professor, Departments of Pharmacology and Chemistry & Biochemistry-UCSD)
UCSD Superfund Research Center
University of California, San Diego
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722