Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes

Stephen Wright, Theresa M. Wunz, Timothy P. Wunz

Research output: Contribution to journalArticle

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Abstract

The renal secretion of organic cations (OCs) involves a carrier-mediated exchange of OC for H+ in the luminal membrane of proximal cells. To assess the influence of chemical structure on the interaction of potential substrates with this process we examined the effect of a series of quaternary ammonium compounds on the transport of the OC tetraethylammonium (TEA) in a preparation of isolated renal brush-border membrane vesicles. Apparent inhibitory potency varied over a factor of 104, as expressed in inhibitor coefficients (KiTEA) whose approximate values ranged from 0.5 μM to 5 mM. The poorest inhibitors of TEA/H+ exchange were those molecules with carboxyl or hydroxyl residues, whereas the addition of methylene groups to a parent molecule tended to increase inhibitory potency. A plot of apparent KiTEA versus calculated octanol:water partition coefficient (expressed in terms of a relative lipophilicity factor) showed a clear correlation between these two parameters, although there was considerable variability between apparent lipophilicity and KiTEA for molecules with very different parent structures. For select groups of molecules with similar parent structures (e.g., the n-tetraalkylammoniums or the 4-phenylpyridinium, 3-phenylpyridinium, and quinolinium compounds) the correlation between calculated lipophilicity and apparent KiTEA was more marked. However, even within these groups of closely related parent structures, there appeared to be subtle, but systematic, variations in inhibitory potency that may have been related to the influence of steric factors on the binding of inhibitors to the TEA/H+ exchanger. We conclude that the lipophilic nature of a quaternary ammonium compound represents the predominant factor in the binding to, and subsequent inhibition of, luminal TEA/H+ exchange. Specific steric factors may influence the binding of substrate to the exchanger, but play a secondary role in this interaction.

Original languageEnglish (US)
Pages (from-to)313-324
Number of pages12
JournalPflugers Archiv European Journal of Physiology
Volume429
Issue number3
DOIs
StatePublished - Jan 1995

Fingerprint

Tetraethylammonium
Brushes
Microvilli
Quaternary Ammonium Compounds
Rabbits
Membranes
Kidney
Cations
Molecules
Quinolinium Compounds
Octanols
Substrates
Hydroxyl Radical
Cell Membrane
Water

Keywords

  • Kidney
  • Organic cation
  • Transport

ASJC Scopus subject areas

  • Physiology

Cite this

Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes. / Wright, Stephen; Wunz, Theresa M.; Wunz, Timothy P.

In: Pflugers Archiv European Journal of Physiology, Vol. 429, No. 3, 01.1995, p. 313-324.

Research output: Contribution to journalArticle

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