Robert H. Tukey
Professor of Pharmacology and Chemistry & Biochemistry
Ph.D., University of Iowa
Our laboratory is investigating molecular and cellular processes that control expression of families of genes involved in xenobiotic and drug metabolism. Much of our work utilizes mouse genetics as a tool to define these processes, which are associated with selective mechanisms that modulate chromatin configuration and transcriptional control. An emphasis is placed on studying the impact of environmental toxicants on genetically modified animal models with the intention of linking regulatory pathways to the onset of a toxic or carcinogenic episode. These approaches have led to a number of projects in the laboratory that can be pursued through graduate student rotations. 1) We have established that developmental expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) is rate-limiting in controlling the metabolism of serum bilirubin and the onset of severe hyperbilirubinemia (jaundice). Experiments are being conducted to examine developmental factors that control UGT1A1, and the CNS events that lead to bilirubin induced demyelination. 2) Developmental regulation of xenobiotic metabolizing genes (XMGs) by transcriptional suppressor proteins is being investigated both in stem cells and XMG knockout mice. 3) Our laboratory has recently discovered that the cell cycle suppressor protein, p53, is regulated during carcinogenesis by endoplasmic reticulum (ER) stress and the UGTs. Projects can be planned to examine the association of the ER specific UGTs with p53 control. 4) Selective environmental toxicants, generated as waste from ubiquitously used personal care products, are shown to function as potent tumor promoters. We are examining the underlying mechanisms behind Triclosan, an antimicrobial agent used in hundreds of personal care products, to induce liver fibrosis and promotion of both liver and colon tumorigenesis.
BMS Focus Areas:
- Liu M. et al. Reduction of p53 by knockout of the UGT1 locus in colon epithelial cells causes an increase in tumorigenesis. CMGH, In Press
- Yueh MF, et al. The commonly used antimicrobial additive triclosan is a liver tumor promoter. PNAS 111: 17200-17205, 2014. PMID:25404284
- Chen S. et al Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc. Natl. Acad. Sci. 110: 19143-19148, 2013. PMID: 24191041.
- Yueh et al. 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.
- Yueh MF et al. Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha. PLoS One. 2012 2:658-67. PMID: 22371261.
- Chen S., et al. Pregnane X receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 mice. Hepatology, 56: 658-67, 2012 PMID: 22371261.
- Fujiwara R et al. Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP-glucuronosyltransfease 1 (UGT1) locus. PNAS 107: 5024-5029, 2010. PMID: 20194756.