Professor of Pharmacology and Chemistry & Biochemistry
Director, UCSD Superfund Basic Research Program
Key Words: Carcinogenesis; Gene Regulation; Signal Transduction
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.
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. doi: 10.1073/pnas.1419119111. Epub 2014 Nov 17. PMID: 25404284; PMCID: PMC4260592
Aoshima N, Fujie Y, Itoh T, Tukey RH, Fujiwara R. Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia. Sci Rep. 2014 Sep 11;4:6343. doi: 10.1038/srep06343. PMID: 25209391; PMCID: PMC4160704
Kutsuno Y, Itoh T, Tukey RH, Fujiwara R. Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice. Drug Metab Dispos. 42:1146-52, 2014. PMID: 4053997.
Maruo Y, Morioka Y, Fujito H, Nakahara S, Yanagi T, Matsui K, Mori A, Sato H, Tukey RH, Takeuchi Y. Bilirubin Uridine Diphosphate-Glucuronosyltransferase Variation Is a Genetic Basis of Breast Milk Jaundice. J Pediatr. 165:36-41, 2014. PMID: 4123958.
Yueh, MF., Chen, S., Nguyen, N., Tukey, RH. Developmental onset of bilirubin-induced neurotoxicity involves Toll-like receptor 2-dependent signaling in humanized UDP-glucuronosyltransferase 1 mice. J Boil Chem. 289:4699-4709, 2014. PMID: 24403077.
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 (CPY-11). Proc. Natl. Acad. Sci. 110: 19143-19148, 2013. PMID: 24191041.
Shibuya, A., Itoh, T., Tukey, R.H., and Fujiwara, R. Impact of fatty acids on human UDO-glucuronosyltransferase 1A1 activity and its expression in neonatal hyperbilirubinemia. Sci Rep. 10.1038/srep02902. 2013. PMID: 24104695
Sumida, K., Kawana, M., Kouno, E., Itoh, T., Takano, S., Narawa, T., Tukey, R.H., Fujiwara, R. Importance of UDP-glucuronosyltransferase 1A1 expression in skin and it induction by UVB in neonatal hyperbilirubinemia. Mol. Pharmacol. 84: 679-686, 2013. PMID: 23950218.
Konopnicki, C. M., Dickmann, L. J., Tracy, J. M., Tukey, R. H., Wienkers, L. C., Foti, R. S. 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: 143-149, 2013 PMID: 23562620.
Fujiwara, R., Chen, S., Karin, M., Tukey, R. H. Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-kappa B leads to hyperbilirubinemia. Gastroenterology. 1: 109-118, 2012. PMC3428231
Yueh, M. F., Li, T., Evans, R. M., Hammock, B., Tukey, R. H. Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor alpha. PLoS One. 6: e37705, 2012. PMC3376094
Li, T., Yu, R.T., Atkins, A. R., Downes, M., Tukey, R. H., Evans, R. M. Targeting the pregnane X receptor in liver injury. Experts Opin Ther Targets. 11: 1075-1083, 2012 PMID: 22913318
Chen, S., Yueh MF, Evans RM, Tukey, R.H. The Pregnane-X-Receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 Mice. Hepatology. 2: 658-667, 2012. PMC3383890
Fujiwara, R., Chen, S., Karin, M., Tukey R.H. IKK/NF-κβ signaling suppresses intestinal UGT1A1 expression inducing neonatal hyperbilirubinemia in humanized UGT1 mice. Gastro. 142: 109-118, 2012. PMC3428231