The role and relevance of proton-coupled oligopeptide transporters in multiple organ systems: Implications for the regional and systemic disposition of peptides/mimetics.

摘要

The mammalian proton-coupled oligopeptide transporter (POT) family currently consists of four members (i.e., PEPT1, PEPT2, PHT1, PHT2). These transporters couple the uphill movement of di- and tripeptides with the downhill movement of protons across biological membranes, via an inwardly-directed proton gradient and negative membrane potential. Because they can accommodate a wide variety of di- and tripeptides, and can transport various pharmacologically active agents (e.g., beta-lactam antibiotics, angiotensin-converting enzyme inhibitors, antiviral nucleoside prodrugs), the POT family has been increasingly recognized with regard to drug design and disposition. Because of their differential tissue expression and wide substrate specificity, a greater understanding of the POT role and relevance in multiple organs is critical. In particular, the strategic localization of PEPT2 to the apical membrane of epithelial cells in the kidney and choroid plexus suggests that it plays an important role in the disposition of peptides/mimetics in the body. Further, little is known about the expression and function of PEPT2 in the retinal pigment epithelium (RPE), a neuroepithelium similar to choroid plexus. The major findings of this dissertation were: (1) PHT1, PHT2 and PEPT2 are present in human and bovine neural retina, while PHT1 is uniquely expressed in the RPE but appears to be localized intracellularly; (2) PEPT2 is responsible for 90-95% of the in vitro uptake of glycylsarcosine and 5-aminolevulinic in choroid plexus whole tissue; (3) in vitro uptake of cefadroxil (beta-lactam antibiotic) in choroid plexus whole tissue is primarily mediated by PEPT2 (80-85%) and to a minor extent by organic anion transporters (10-15%); (4) PEPT2 operates in vivo as an efflux transporter in choroid plexus; (5) PEPT2 is the predominant peptide transporter in the kidney and provides the "driving force" for distribution of dipeptides to important tissues and fluids (e.g., brain and CSF). The combined effort of PEPT2 in the kidney and brain may influence the sensitivity or toxicity to peptide-like drugs, and as a result, the rational design of new peptide-like pharmaceuticals may need to take into account affinity for PEPT2. This research provides a foundation for research efforts directed towards the exploitation of PEPT2 for innovative drug delivery and tissue-targeting strategies.