Comparison of human and monkey peptide transporters: PEPT1 and PEPT2.
Human proton-dependent peptide transporters, PEPT1 and PEPT2, mediate the cellular uptake of di- and tripeptides as well as a variety of drug molecules. Although PEPT1 and PEPT2 have been cloned from many species, there are no data available for monkey, an important pharmacological and preclinical species in drug development. In this study, it was first verified that monkey intestine transports a model dipeptide, Gly-Sar, in a proton-dependent manner (0.30 +/- 0.05 pmol cm(-2) s(-1) at pH 6.0 and 0.10 +/- 0.03 pmol cm(-2) s(-1) at pH 7.4) in the absorptive direction, presumably by monkey PEPT1. RT-PCR and rapid amplification of cDNA ends (RACE) were then used to clone monkey PEPT1 and PEPT2. Monkey PEPT1 (2127 bp and 708 amino acids) was found to be >94 and > 92% identical to human PEPT1 at the cDNA and amino acid level, respectively. Monkey PEPT2 (2190 bp and 729 amino acids) was found to be > 97% identical to human PEPT2 at both the cDNA and amino acid levels. Functional comparison of human and monkey peptide transporters expressed in HeLa cells suggested that functionalities of PEPT1 and PEPT2 were largely conserved in terms of Gly-Sar uptake kinetics and inhibitor specificity (for most tested substrates). Finally, Northern and RT-PCR analyses revealed some differences in tissue mRNA levels of peptide transporters between human and monkey.
Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Eric Y
EY
Zhang
Richard M
RM
Emerick
Youngeen A
YA
Pak
Steven A
SA
Wrighton
Kathleen M
KM
Hillgren
D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004151:Dipeptides / Q000494:pharmacology; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007583:Jejunum / Q000378:metabolism; D007700:Kinetics; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D000074011:Peptide Transporter 1; D011522:Protons; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D027981:Symporters / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D004151:Dipeptides; D000074011:Peptide Transporter 1; D011522:Protons; D012333:RNA, Messenger; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; C004194:glycylsarcosine