Metabolite transport

Drug elimination is an important detoxification function of the liver. During their metabolism compounds are transformed into more water-soluble conjugates via phase 1 and 2 biotransformation processes accomplished by cytochrome P450 and transferase enzymes, including UDP-glucuronosyl transferases (UGTs). UGTs transfer glucuronic acid from the co-substrate, the UDP glucuronic acid (UDPGA), to the phase 1 metabolized compound generating glucuronides, which are facilitated for excretion. As the catalytic side of UGTs is located in the lumen of the endoplasmic reticulum (ER), the co-substrate UDPGA of glucuronidation reactions needs to be translocated from its site of synthesis, the cytosol, to the ER lumen. As this hydrophilic, bulky, and negatively charged substrate is not favored for passive diffusion, it necessitates carrier-mediated transport through the ER membrane to ensure proper UGT function. Furthermore, UGT-generated glucuronides exhibit poor membrane permeability and are not able to cross the ER membrane by simple diffusion and therefore also necessitate carrier mediated transport to reach their site of excretion at the hepatocellular plasma membrane. Although strong evidence for the existence of multiple transport proteins in the ER membrane responsible for UDPGA and/or UGT-generated glucuronide transport through the ER membrane is given, their identity remains unknown. Therefore, the proposed project focuses on the functional characterization of putative UDPGA and glucuronide transporting protein(s) and their subsequent molecular identification. The findings of this project will close important gaps in the understanding of detoxification processes accomplished by the liver and will lay the basis for a better understanding in the occurrence of drug induced interactions, side or even toxic effects as well as diseases caused by defects in this detoxification process like hyperbilirubinemia.