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Research Interests

My research interests revolve around a family of enzymes called cytochrome P450 enzymes. The word "cytochrome" means they absorb light in the visible range (because of this P450s are red in color). The ability of P450 enzymes to absorb light in the visible range comes from the fact that P450 enzymes are heme-containing enzymes. The term "P450" comes from their initial purification where the "P" stands for pigment and "450" stands for the wavelength of light they absorb under certain conditions. Finally, enzymes are proteins that catalyze chemical reactions. With these definitions, it is easier to refer to them as "P450 enzymes."

The P450 enzymes are found in organisms from bacteria to plants to humans. In humans, P450 enzymes are most abundant in the liver where they work to clear the body of foreign substances. However, P450 enzymes are found in every human tissue except skeletal muscle and red blood cells.

When the human genome was sequenced, 57 different P450 enzyme sequences were identified; for all but 13 of these, the function is known. The known functions of P450 enzymes include metabolism of steroids, fatty acids, 20-carbon molecules (called eicosanoids - which, among other things, cause pain and inflammation), vitamin A and D, and the many foreign small molecules that enter the body every day. This last target category - foreign bodies, or more appropriately xenobiotics, includes things such as pharmaceutical drugs, complex plant alkaloids (as in fruits, vegetables, herbal supplements, etc.), illicit drugs, pollutants (such as pesticides, etc.), products of combustion (such as in cigarette smoke or charred meat), ethanol, carcinogens, and an unlimited number of other small organic molecules.

Given the important roles of these enzymes in many processes, inhibition of the P450 enzymes in humans may be important for disease prevention (e.g., prevention of carcinogen formation or modulation of steroid production in breast cancer, etc.) and a concern for drug metabolism (e.g., loss or gain of pharmaceutical drug efficacy). Inhibition can be of a reversible or irreversible nature with irreversible inhibition having longer-term effects.

The goal of my research is to describe inactivation of P450 enzymes by compounds believed to be irreversible, so called mechanism-based inhibitors. Mechanism-based inhibitors of P450 enzymes are useful in the basic research of P450 structure, mechanism, and regulation. Mechanism-based inhibitors are also of interest clinically due to their ability to cause unfavorable drug-drug induced events or to modulate activity of other drugs.

 

See Curriculum Vitae for list of recent publications with undergraduate student co-authors.

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