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Project 4

The Expression in Mice of Human Xenobiotic Drug Metabolizing Genes Responsive to Ah Receptor Toxicants

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Dr. Robert Tukey

Superfund site chemicals such as polycyclic aromatic hydrocarbons (PAHs), halogenated aromatic hydrocarbons (HAHs) and polychlorinated biphenyls (PCBs) are known human health toxicants. Their toxicity is associated with altered gene expression. The molecular mechanisms that underlie gene activation by these agents are linked to activation of the dioxin or aryl hydrocarbon (Ah) receptor (AhR). AhR ligands signal gene activation by modifying other signal transduction pathways such as those under the regulation of protein kinase C (PKC). Project investigators are examining the actions of AhR ligands on gene expression and are developing a sensitive AhR ligand reporter gene system. This AhR-reporter gene system will be useful as a model for monitoring the presence of AhR ligands in mixtures. To further understand the underlying mechanisms associated with AhR ligand toxicity, project experiments will characterize genes that are targeted by AhR dependent mechanisms, and those that are coordinately regulated by PKC and a sequence-specific transcriptional activator (AP-1). The Microarray Technology Core will be utilized to determine which genes have been modified by these toxicants. Finally, to study the functional role of some of the altered genes, researchers will knock-out selected genes in mice. Investigators will collaborate with other projects to develop an understanding of the signal transduction pathways involved in the toxic actions of these agents.

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Dr. Robert Tukey
University of California, San Diego


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Recent Publications and Documents

Nguyen, N., Bonzo, J.A., Chen, S., Chouinard, S., Kelner, M., Hardiman, G., Belanger, A., and Tukey, R.H. Disruption of the Ugt1 locus in mice resembles human Crigler-Najjar type I disease. J. Biol. Chem. 283:7901-7911, 2008.
PubMed ID: 18180294

Bonzo, J.A., Belanger, A., and Tukey, R.H. 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, 2007.
PubMed ID: 17256720

Operaņa TN, Nguyen N, Chen S, Beaton D and Tukey RH. Human CYP1A1GFP expression in transgenic mice serves as a biomarker for environmental toxicant exposure. Toxicological Sciences 95: 98-107, 2007.
PubMed ID: 17065433

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. 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, 2007.
PubMed ID: 17151188

Yueh, M-F. and Tukey, R.H. Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice. J. Biol. Chem. 282: 8749-8758, 2007.
PubMed ID: 17259171

Verreault, M., Senekeo-Effenberger, K., Trottier, J., Bonzo, J.A., Belanger, J., Kaeding, J., Staels, B., Caron, P., Tukey, R.H. and Barbier, O. The liver X-receptor alpha controls hepatic expression of the human bile acid-glucuronidating UGT1A3 enzyme in human cells and transgenic mice. Hepatology, 44: 367-378, 2006. 
PubMed ID: 16871576

Bonzo JA, Chen S, Galijatovic A, Tukey RH. Arsenite inihibition of CYP1A1 induction by TCDD is independent of cell cycle arrest. Mol. Pharm. 67:  1247-1256, 2005.
PubMed ID: 15630080

Chen S, Beaton D, Nguyen N, Senekeo-Effenberger K, Brace-Sinnokrak E, Argikar U, Remmel RP, Trottier J, Barbier O, Ritter J, Tukey RH. Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltranserase-1 (UGT1) locus. J. Biol. Chem. 280: 37547-37557, 2005.
PubMed ID: 16155002

Chen S, Operana T, Bonzo J, Nguyen N, Tukey RH. Erk kinase inhibition stabilizes the aryl hydrocarbon receptor. J. Biol. Chem. 280:  4350-4359, 2005.
PubMed ID: 15572374

Machemer DEW and Tukey RH. The role of protein kinase C in regulation of TCDD-mediated CYP1A1 gene expression. Toxicological Sciences 87:  27-37, 2005.
PubMed ID: 15947024