Skip to main content
Log in

Differential Recognition of ACE Inhibitors in Xenopus Laevis Oocytes Expressing Rat PEPT1 and PEPT2

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. To examine the mechanism of inhibition of glycylsarcosine(GlySar) transport by quinapril and enalapril, and whether or notangiotensin converting enzyme (ACE) inhibitors are transported by PEPT2as well as by PEPT1.

Methods. Xenopus laevis oocytes were cRNA-injected with rat PEPT1or PEPT2 and the transport kinetics of radiolabeled GlySar were studiedin the absence and presence of quinapril and enalapril. Thetwo-microelectrode voltage-clamp technique was also performed to probe theelectrogenic uptake of captopril, quinapril and enalapril.

Results. Kinetic analyses demonstrated that quinapril inhibited theuptake of GlySar in a noncompetitive manner in Xenopus oocytesinjected with PEPT1 or PEPT2 (Ki = 0.8 or 0.4 mM, respectively).In contrast, a competitive interaction was observed between GlySarand enalapril (Ki = 10.8 mM for PEPT1 or 4.3 mM for PEPT2).Most significantly, captopril and enalapril, but not quinapril, inducedinwardly-directed currents in both PEPT1- and PEPT2-expressedoocytes.

Conclusions. These results are unique in providing direct evidence forthe substrate recognition and transport of some ACE inhibitors by thehigh- and low-affinity oligopeptide transporters. Our findings point todifferences between PEPT1 and PEPT2 in their affinity to, rather thanin their specificity for, ACE inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. M. Boll, D. Markovich, W.-M. Weber, H. Korte, H. Daniel, and H. Murer. Expression cloning of a cDNA from rabbit small intestine related to proton-coupled transport of peptides, β-lactam antibiotics and ACE-inhibitors. Pflügers Arch.· Eur. J. Physiol. 429:146–149 (1994).

    Google Scholar 

  2. M. Boll, M. Herget, M. Wagener, W. M. Weber, D. Markovich, J. Biber, W. Clauss, H. Murer, and H. Daniel. Expression cloning and functional characterization of the kidney cortex high-affinity proton-coupled peptide transporter. Proc. Natl. Acad. Sci. 93: 284–289 (1996).

    Google Scholar 

  3. Y.-J. Fei, Y. Kanai, S. Nussberger, V. Ganapathy, F. H. Leibach, M. F. Romero, S. K. Singh, W. F. Boron, and M. A. Hediger. Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368:563–566 (1994).

    Google Scholar 

  4. K.-I. Miyamoto, T. Shiraga, K. Morita, H. Yamamoto, H. Haga, Y. Taketani, I. Tamai, Y. Sai, A. Tsuji, and E. Takeda. Sequence, tissue distribution and developmental changes in rat intestinal oligopeptide transporter. Biochim. Biophys. Acta 1305:34–38 (1996).

    Google Scholar 

  5. H. Saito, M. Okuda, T. Terada, S. Sasaki, and K.-I. Inui. Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of β-lactam antibiotics in intestine and kidney. J. Pharmacol. Exp. Ther. 275:1631–1637 (1995).

    Google Scholar 

  6. H. Saito, T. Terada, M. Okuda, S. Sasaki, and K.-I. Inui. Molecular cloning and tissue distribution of rat peptide transporter PEPT2. Biochim. Biophys. Acta 1280:173–177 (1996).

    Google Scholar 

  7. R. Liang, Y.-J. Fei, P. D. Prasad, S. Ramamoorthy, H. Han, T. L. Yang-Feng, M. A. Hediger, V. Ganapathy, and F. H. Leibach. Human intestinal H+/peptide cotransporter: Cloning, functional expression, and chromosomal localization. J. Biol. Chem. 270:6456–6463 (1995).

    Google Scholar 

  8. W. Liu, R. Liang, S. Ramamoorthy, Y.-J. Fei, M. E. Ganapathy, M. A. Hediger, V. Ganapathy, and F. H. Leibach. Molecular cloning of PEPT 2, a new member of the H+/peptide cotransporter family, from human kidney. Biochim. Biophys. Acta 1235:461–466 (1995).

    Google Scholar 

  9. S. A. Adibi. The oligopeptide transporter (Pept-1) in human intes-tine: Biology and function. Gastroenterology 113:332–340 (1997).

    Google Scholar 

  10. S. A. Adibi. Renal assimilation of oligopeptides: Physiological mechanisms and metabolic importance. Am. J. Physiol. 272: E723–E736 (1997).

    Google Scholar 

  11. F. H. Leibach and V. Ganapathy. Peptide transporters in the intestine and the kidney. Annu. Rev. Nutr. 16:99–119 (1996).

    Google Scholar 

  12. T. Yamashita, S. Shimada, W. Guo, K. Sato, E. Kohmura, T. Hayakawa, T. Takagi, and M. Tohyama. Cloning and functional expression of a brain peptide/histidine transporter. J. Biol. Chem. 272:10205–10211 (1997).

    Google Scholar 

  13. C. S. Temple and C. A. R. Boyd. Proton-coupled oligopeptide transport by rat renal cortical brush border membrane vesicles: A functional analysis using ACE inhibitors to determine the isoform of the transporter. Biochim. Biophys. Acta 1373:277–281 (1998).

    Google Scholar 

  14. W. Akarawut, C.-J. Lin, and D. E. Smith. Noncompetitive inhibition of glycylsarcosine transport by quinapril in rabbit renal brush border membrane vesicles: Effect on high-affinity peptide transporter. J. Pharmacol. Exp. Ther. 287:684–690 (1998).

    Google Scholar 

  15. C.-J. Lin, W. Akarawut, and D. E. Smith. Competitive inhibition of glycylsarcosine transport by enalapril in rabbit renal brush border membrane vesicles: Interaction of ACE inhibitors with high-affinity H+/peptide symporter. Pharm. Res. 16:609–615 (1999).

    Google Scholar 

  16. D. E. Smith, A. Pavlova, U. V. Berger, M. A. Hediger, T. Yang, Y. G. Huang, and J. B. Schnermann. Tubular localization and tissue distribution of peptide transporters in rat kidney. Pharm. Res. 15:1244–1249 (1998).

    Google Scholar 

  17. H. Shen, D. E. Smith, T. Yang, Y. G. Huang, J. B. Schnermann, and F. C. Brosius III. Localization of PEPT1 and PEPT2 proton-coupled oligopeptide transporter mRNA and protein in rat kidney. Am. J. Physiol. 276:F658–F665 (1999).

    Google Scholar 

  18. H. Gunshin, B. Mackenzie, U. V. Berger, Y. Gunshin, M. F. Romero, W. F. Boron, S. Nussberger, J. L. Gollan, and M. A. Hediger. Cloning and characterization of a mammalian proton-coupled metalion transporter. Nature 388:482–488 (1997).

    Google Scholar 

  19. X.-Z. Chen, C. Shayakul, U. V. Berger, W. Tian, and M. A. Hediger. Characterization of a rat Na+-dicarboxylate cotransporter. J. Biol. Chem. 273:20972–20981 (1998).

    Google Scholar 

  20. X.-Z. Chen, T. Zhu, D. E. Smith, and M. A. Hediger. Stoichiometry and kinetics of the high-affinity H+-coupled peptide transporter PEPT2. J. Biol. Chem. 274:2773–2779 (1999).

    Google Scholar 

  21. I. Saadi, X.-Z. Chen, M. A. Hediger, P. Ong, P. Perreira, P. Goodyer, and R. Rozen. Molecular genetics of cystinuria: Mutation analysis of SLC3A1 and evidence for another gene in type I (silent) phenotype. Kidney Int. 54:48–55 (1998).

    Google Scholar 

  22. C. J. Seal and D. S. Parker. Isolation and characterization of circulating low molecular weight peptides in steer, sheep and rat portal and peripheral blood. Comp. Biochem. Physiol. 99:679–685 (1991).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, T., Chen, XZ., Steel, A. et al. Differential Recognition of ACE Inhibitors in Xenopus Laevis Oocytes Expressing Rat PEPT1 and PEPT2. Pharm Res 17, 526–532 (2000). https://doi.org/10.1023/A:1007556630189

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007556630189

Navigation