Regulation of drug transport proteins and drug metabolizing enzymes by nuclear receptors

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In the traditional view drug molecules were thought to enter cells by simply passing through the cell membrane to access intracellular drug targets. Advances in molecular biology have clearly established that membrane proteins called drug transporters facilitate the uptake of drugs into cells as well as the extrusion of drugs out of cells. Together these uptake and efflux drug transporters form a molecular gateway to the entrance and exit of drug molecules from the cell. These drug transporters are now realized as well established determinants of the intracellular concentration of drugs and are therefore important determinants of drug response and efficacy. It has been well established that the amount and activity of drug transporter protein at the cell surface is under tight control by intracellular factors known as nuclear receptors. Despite many recent advances in our understanding of nuclear receptor biology, the processes that mediate the strict control over the amount of drug transporter protein at the cell surface remain poorly understood. We are studying the processes that control the amount and activity of drug transporter protein in the cell. Our studies will involve the evaluation of epigenetic changes to nuclear receptors and the resultant effect on drug transport genes and proteins. Epigenetics is a relatively new area of research that focuses on the study of changes in gene expression that are not due to changes in the sequence of DNA. Many epigenetic changes are believed to be mediated by the environment. In addition to evaluating the effect of changes to the amount of drug transporter genes and proteins at the cell surface we will also determine the effect on function by using well established drug transport assays. Determining how epigenetics intersects with nuclear receptors to regulate the amount and activity of drug transport proteins on cells will allow us to better understand how drugs reach their molecular targets and will aid in better guidance of drug design and predictability of response.