Differential recognition of ACE inhibitors in Xenopus laevis oocytes expressing rat PEPT1 and PEPT2.
OBJECTIVE
To examine the mechanism of inhibition of glycylsarcosine (GlySar) transport by quinapril and enalapril, and whether or not angiotensin converting enzyme (ACE) inhibitors are transported by PEPT2 as well as by PEPT1.


METHODS
Xenopus laevis oocytes were cRNA-injected with rat PEPT1 or PEPT2 and the transport kinetics of radiolabeled GlySar were studied in the absence and presence of quinapril and enalapril. The two-microelectrode voltage-clamp technique was also performed to probe the electrogenic uptake of captopril, quinapril and enalapril.


RESULTS
Kinetic analyses demonstrated that quinapril inhibited the uptake of GlySar in a noncompetitive manner in Xenopus oocytes injected with PEPT1 or PEPT2 (Ki = 0.8 or 0.4 mM, respectively). In contrast, a competitive interaction was observed between GlySar and enalapril (Ki = 10.8 mM for PEPT1 or 4.3 mM for PEPT2). Most significantly, captopril and enalapril, but not quinapril, induced inwardly-directed currents in both PEPT1- and PEPT2-expressed oocytes.


CONCLUSIONS
These results are unique in providing direct evidence for the substrate recognition and transport of some ACE inhibitors by the high- and low-affinity oligopeptide transporters. Our findings point to differences between PEPT1 and PEPT2 in their affinity to, rather than in their specificity for, ACE inhibitors.
Zhu
T
T
College of Pharmacy and Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor 48109-0504, USA.
Chen
X Z
XZ
Steel
A
A
Hediger
M A
MA
Smith
D E
DE
D000465:Algorithms; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D003001:Cloning, Molecular; D004151:Dipeptides / Q000378:metabolism; D004594:Electrophysiology; D007700:Kinetics; D009865:Oocytes / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D000074011:Peptide Transporter 1; D051381:Rats; D027981:Symporters; D014982:Xenopus laevis
D000806:Angiotensin-Converting Enzyme Inhibitors; D002352:Carrier Proteins; D004151:Dipeptides; D000074011:Peptide Transporter 1; C489940:Slc15a1 protein, rat; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; C004194:glycylsarcosine