TY - JOUR

T1 - Di/tri-peptide transporters as drug delivery targets

T2 - regulation of transport under physiological and patho-physiological conditions

AU - Nielsen, C U

AU - Brodin, Birger

PY - 2003

Y1 - 2003

N2 - Two human di/tri-peptide transporters, hPepT1 and hPepT2 have been identified and functionally characterized. In the small intestine hPepT1 is exclusively expressed, whereas both PepT1 and PepT2 are expressed in the proximal tubule. The transport via di/tri-peptide transporters is proton-dependent, and the transporters thus belong to the Proton-dependent Oligopeptide Transporter (POT)-family. The transporters are not drug targets per se, however due to their uniquely broad substrate specificity; they have proved to be relevant drug targets at the level of drug transport. Drug molecules such as oral active beta-lactam antibiotics, bestatin, prodrugs of aciclovir and ganciclovir have oral bioavailabilities, which largely are a result of their interaction with PepT1. In the last few years an increasing number of studies concerned with regulation of di/tri-peptide transporter capacity have appeared. Studies on receptor-mediated regulation has shown that both PepT1 and PepT2 is down-regulated by long-term exposure to epidermal growth factor (EGF) due to a decreased gene transcription. PepT1-mediated transport is up-regulated by certain substrates and in response to fasting and starvation at the level of increased gene transcription. PepT1-mediated transport is up-regulated by short-term exposure to receptor agonists such as EGF, insulin, leptin, and clonidine, and down-regulated by VIP. Overall, the regulation of di/tri-peptide transport may be contributed to 1) changes in apical proton-motive force 2) recruitment of di/tri-peptide transporters from vesicular storages 3) changes in gene transcription/mRNA stability. The aim of the present review is to discuss physiological, patho-physiological and drug-induced regulation of di/tri-peptide transporter mediated transport.

AB - Two human di/tri-peptide transporters, hPepT1 and hPepT2 have been identified and functionally characterized. In the small intestine hPepT1 is exclusively expressed, whereas both PepT1 and PepT2 are expressed in the proximal tubule. The transport via di/tri-peptide transporters is proton-dependent, and the transporters thus belong to the Proton-dependent Oligopeptide Transporter (POT)-family. The transporters are not drug targets per se, however due to their uniquely broad substrate specificity; they have proved to be relevant drug targets at the level of drug transport. Drug molecules such as oral active beta-lactam antibiotics, bestatin, prodrugs of aciclovir and ganciclovir have oral bioavailabilities, which largely are a result of their interaction with PepT1. In the last few years an increasing number of studies concerned with regulation of di/tri-peptide transporter capacity have appeared. Studies on receptor-mediated regulation has shown that both PepT1 and PepT2 is down-regulated by long-term exposure to epidermal growth factor (EGF) due to a decreased gene transcription. PepT1-mediated transport is up-regulated by certain substrates and in response to fasting and starvation at the level of increased gene transcription. PepT1-mediated transport is up-regulated by short-term exposure to receptor agonists such as EGF, insulin, leptin, and clonidine, and down-regulated by VIP. Overall, the regulation of di/tri-peptide transport may be contributed to 1) changes in apical proton-motive force 2) recruitment of di/tri-peptide transporters from vesicular storages 3) changes in gene transcription/mRNA stability. The aim of the present review is to discuss physiological, patho-physiological and drug-induced regulation of di/tri-peptide transporter mediated transport.

KW - Animals

KW - Biological Transport

KW - Carrier Proteins

KW - Diabetes Mellitus

KW - Dipeptides

KW - Drug Delivery Systems

KW - Enterocolitis

KW - Humans

KW - Intestine, Small

KW - Kidney Tubules, Proximal

KW - Neoplasms

KW - Oligopeptides

KW - Symporters

M3 - Journal article

C2 - 12816347

VL - 4

SP - 373

EP - 388

JO - Current Drug Targets

JF - Current Drug Targets

SN - 1389-4501

IS - 5

ER -