The major research interests in Dr. Omiecinski's laboratory are centered in molecular toxicology. The laboratory is engaged in several projects studying the regulation and genetics of biotransformation enzymes, including the cytochrome P450s and epoxide hydrolases. These enzymes actively detoxify or otherwise biotransform a broad array of foreign chemicals, including many pharmaceutical agents, environmental contaminants, and endogenous substances. These processes ultimately determine the reactive fate of chemicals in human and animal tissues. The respective genes are subjected to complex tissue-specific control, developmental regulation, and differential transcriptional activation upon stimulation with chemical inducing agents. Chemical exposures can result in disruption of basal gene expression patterns, alterations in rates of metabolism, and altered susceptibility of an organism to the effects of drugs or toxicants.
One research project is focused on delineation of transcriptional control mechanisms regulating induction of P450 genes by phenobarbital. This agent serves as a prototype for a class of compounds exhibiting pleiotropic effects in mammalian liver cells, effects that include transcriptional activation of a battery of genes. Various strategies, including reporter gene assays in cultured primary hepatocytes, transgenic mouse models, assessment of DNA-protein/ protein-protein interactions, and signal transduction analyses are in use to delineate molecular mechanisms regulating induction and expression of these critical pathways.
Another major research focus of the laboratory involves the study of genetic polymorphism, in particular for the epoxide hydrolases and esterases. Genetic polymorphisms for several biotransformation enzymes have been characterized in human populations, and may result in "rapid" or "poor" metabolizer phenotype. The laboratory has characterized genetic variation in serum paraoxonase, microsomal epoxide hydrolase, and most recently, in soluble form of epoxide hydrolase. In association with a National Institute of Environmental Health Sciences Center of Excellence Program, high throughput genotyping approaches have been deployed for use in molecular epidemiological investigations to assess potential genetic factors that may predispose individuals to toxic effects associated with chemical or drug exposures.
For additional information on the EcoGenetics Center,
see:
http://depts.washington.edu/ceeh/
Hassett C, Sidhu
JS, Aicher L, Omiecinski CJ. Human microsomal epoxide hydrolase:
genetic polymorphism and functional expression of amino acid
variants in vitro. Human Molecular Genetics
3: 421-428, 1994.
Sidhu JS,
Omiecinski CJ. Protein synthesis inhibitors exhibit a non-specific
effect on phenobarbital-inducible cytochrome P450 gene expression
in primary rat hepatocytes. J Biological Chemistry 273: 4769-4775,
1998.
Raaka S, Hassett
C, Omiecinski CJ. Human microsomal epoxide hydrolase: 5'-flanking
region genetic polymorphisms. Carcinogenesis 19: 387-393, 1998.
Omiecinski CJ,
Remmel RP, Hosagrahara VP. Concise review of the cytochrome
P450s and their roles in toxicology. Toxicological Sciences 48:
151-156, 1999.
Ramsden R, Beck
NA, Sommer KM, and Omiecinski, CJ. Phenobarbital responsiveness
conferred by the rat CYP2B2 5'-flanking region in transgenic mice.
Gene 228: 169-179, 1999.
Beck NB,
Omiecinski CJ. Lack of modulation by phenobarbital of cyclic AMP
levels or protein kinase A activity in rat primary hepatocytes.
Biochemical Pharmacology 58: 1109-1114, 1999.
Krovat
BC, Tracy JH, Omiecinski CJ. Fingerprinting of cytochrome P450
and microsomal epoxide hydrolase gene expression in human blood
cells. Toxicological Sciences 55: 352-360, 2000.
Beck NB, Sidhu JS, Omiecinski CJ. Baculovirus vectors repress phenobarbital-mediated gene induction and stimulate cytokine expression in primary cultures of rat hepatocytes. Gene Therapy 7: 1274-1283, 2000.
Schilter B, Andersen MR, Acharya C, Omiecinski CJ. Activation of cytochrome P450 gene expression in the rat brain by phenobarbital-like inducers. J Pharm Exptl Therapeut 294: 916-922, 2000.
Sandberg M, Hassett C, Adman ET, Meijer J, Omiecinski CJ. Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms. J Biological Chemistry 275: 28873-28881, 2000.
Yamada H, Matsunaga H, Tsuji K, Matsumoto S, Yamamoto M, Ishii Y, Omiecinski CJ, Oguri K. Sequence analyses of CYP2B genes and catalytic profiles for P450s in Qdj:Sprague-Dawley rats that lack response to the phenobarbital-mediated induction of CYP2B, Arch Biochem Biophys 292: 986-993, 2000.
Sidhu JS, Liu F, Boyle SM, Omiecinski CJ. PI3K inhibitors reverse the suppressive actions of insulin on CYP2E1 expression by activating stress-response pathways in primary rat hepatocytes, Molecular Pharmacology 59: 1-9, 2001.
For additional
information and publication listings for this research program,
see:
http://depts.washington.edu/phcol/fac/omiecinski.html
http://expertise.cos.com/cgi-bin/exp.chi?id=373897
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