Description): Hepatic metabolism and secretion of endobiotic and xenobiotic substances are essential functions of the liver, and hepatobiliary secretion into bile is the major excretory route for numerous pharmacologic agents. Many commonly used drugs are Type I organic cation amines, which are transported into the liver via a transport protein termed Oct1. In humans, Oct1 is expressed almost exclusively in the liver, further indicating the importance of the liver for the elimination of Type I organic cationic drugs. Although Type I organic cationic drugs are pharmacologic agents that are commonly used in both premature infants as well as neonatal and pediatric populations, little is known about the developmental expression of Oct1 in normal physiology or in pathophysiological states; and the mechanisms of gene regulation of Oct1 remain virtually unexplored. Therefore, the objectives of this project are to employ murine models and human liver tissue samples to examine the developmental regulation of Oct1, and determine the mechanisms of gene regulation during the ontogenic expression of this essential hepatic transporter. The investigators will initially employ murine models to further characterize the kinetics of hepatic Type I organic cation uptake and expression of mouse Oct1 in normal development, and determine the pharmacologic effect of these changes in experimental pathophysiological states, as well as in models with reduced hepatic Oct1 expression. They will clone the mouse Oct1 promoter and employ 5'-deletional analysis to study the transcriptional gene regulation of murine Oct1. Subsequently they will determine the mechanisms of gene regulation of human Oct1 in normal development and pediatric disease states. Finally, they will develop transgenic mice that employ Oct1 promoter-reporter gene constructs to determine the cis-acting regulatory elements that are essential for the ontogenic expression of Oct1. These studies will have direct implications on our understanding of the physiology, developmental pharmacology, and mechanisms of regulation of the hepatic Oct1 transporter. This knowledge will be critical for the development of rational pharmacologic and therapeutic approaches of the many organic cationic drugs used in the neonatal and pediatric population.
