Curt Omiecinski, PhD

Research:

The research in our laboratory is focused on the molecularbiology of mammalian biotransformation. Variability in the expression of biotransformation activities appears to substantially impact individual responsiveness to both pharmaceutical and toxicant exposures. One line of laboratory endeavor relates to the study of the regulatory mechanisms responsible for controlling the expression of the biotransformation enzymes. Recently, a variety of ligand-activated nuclear receptors have been characterized that serve as “xenosensors” in mammalian cells and function as transcriptional activators of a variety of genes, including the cytochrome P450s. The P450s are key components of the drug and chemical metabolism pathway. Phenobarbital (PB) is an example of clinical compound that produces marked activation of the expression of several P450 genes, in a process that is regulated by the constitutive androstane receptor (CAR). The laboratory studies signaling cascades activated by inducer exposures and nuclear events dictating altered DNA-protein and protein-protein interactions associated with the induction process. Experimental models in use include primary hepatocyte cultures and transgenic mouse systems. Investigations are underway examining the transcriptional activation processes involved in gene induction, such as the interactions of nuclear receptors with core DNA enhancer elements and the associated network of nuclear co-activator and co-repressor proteins. We are very interested in determining genetic variation in nuclear receptor structure that may impact important clinical and toxicological outcomes.

A parallel investigation in the laboratory involves the characterization of the human epoxide hydrolases, including their structure, regulation and genetic variability. These enzymes, like the P450s, also function to biotransform a variety of drug and toxic substances, typically acting upon epoxide intermediates produced by P450 reactions. Epoxide hydrolase often functions to render the epoxides less chemically reactive. Two forms of human hydrolase are being studied, the microsomal epoxide hydrolase and the soluble epoxide hydrolase. The microsomal enzyme is active against a broad array of xenobiotic chemicals whereas the soluble enzyme principally participates in the metabolism of endogenous substances such as the arachidonate derivates, the epoxyeicosotrienoic acids. Our epoxide hydrolase research program involves characterization of genetic variation, structure-function relationships, and tissue-specific regulation of their expression.