Nielsen C U, Brodin B
Department of Pharmaceutics, The Danish University of Pharmaceutical Sciences, 2-Universitetsparken, DK-2100 Copenhagen, Denmark.
Curr Drug Targets. 2003 Jul;4(5):373-88. doi: 10.2174/1389450033491028.
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.
已鉴定出两种人二肽/三肽转运体，即hPepT1和hPepT2，并对其功能特性进行了表征。在小肠中，hPepT1是唯一表达的，而PepT1和PepT2在近端小管中均有表达。通过二肽/三肽转运体的转运是质子依赖性的，因此这些转运体属于质子依赖性寡肽转运体（POT）家族。这些转运体本身并非药物靶点，然而，由于其独特的广泛底物特异性，它们已被证明在药物转运水平上是相关的药物靶点。诸如口服活性β-内酰胺抗生素、贝他汀、阿昔洛韦和更昔洛韦的前药等药物分子具有口服生物利用度，这在很大程度上是它们与PepT1相互作用的结果。在过去几年中，出现了越来越多关于二肽/三肽转运体能力调节的研究。受体介导的调节研究表明，由于基因转录减少，长期暴露于表皮生长因子（EGF）会使PepT1和PepT2均下调。PepT1介导的转运在基因转录增加的水平上受到某些底物以及禁食和饥饿的上调。PepT1介导的转运受到短期暴露于受体激动剂如EGF、胰岛素、瘦素和可乐定的上调，而受到血管活性肠肽（VIP）的下调。总体而言，二肽/三肽转运的调节可能归因于：1）顶端质子动力的变化；2）从囊泡储存中募集二肽/三肽转运体；3）基因转录/mRNA稳定性的变化。本综述的目的是讨论二肽/三肽转运体介导的转运的生理、病理生理和药物诱导的调节。
