Carrier-mediated transport system for choline and its related quaternary ammonium compounds on rat intestinal brush-border membrane

Shinmoto, Hiroshi; Kobayashi, Mariko; Sugawara, Mitsuru; Iseki, Ken; Miyazaki, Katsumi

doi:10.1016/0005-2736(92)90265-n

Cited by 38 publications

(17 citation statements)

References 31 publications

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“…However, it is possible that the choline and the [ 3 H]MPP + transporter are not two distinct transporters, but instead that the differences observed reflect differences between the two experimental models. In this context, it is important to note that the choline transporter was described in isolated brush-border membrane vesicles from rat small intestine (Kessler et al 1978;Saitoh et al 1992), and that Caco-2 cells are derived from human colon.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the transport of the organic cation [ 3 H]MPP + in human intestinal epithelial (Caco-2) cells

Martel

Calhau

Azevedo

2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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The aim of this study was to characterize the transport of organic cations at the intestinal level, by studying the characteristics of the transport of 1-methyl-4-phenylpyridinium (MPP+) in Caco-2 cells. Transepithelial flux as well as cellular accumulation of [3H]MPP+ were quantitatively similar when substrate was applied from the basolateral or apical cell membrane. Verapamil (100 microM) and rhodamine123 (10 microM) significantly reduced [3H]MPP+ transepithelial flux in the apical-to-basolateral direction. When cells were grown on plastic supports, [3H]MPP+ was rapidly accumulated in the cells, both by saturable and nonsaturable mechanisms. The kinetic parameters of the saturable component were: Km: 449 microM and Vmax: 2,249 pmol per mg protein and 5 min. Uptake of [3H]MPP+ was metabolic energy-dependent and Na+-, pH- and potential-independent. It was inhibited by several organic cations (verapamil, rhodamine123, daunomycin, vinblastine, tetrabutylammonium and vecuronium) but not by others (tetraethylammonium and N-methylnicotinamide). Decynium22 and corticosterone inhibited [3H]MPP+ uptake into the cells. The P-glycoprotein antibody UIC2 (20 microg/ml) had no effect. In conclusion, [3H]MPP+ is efficiently transported by Caco-2 cells in both basolateral-to-apical (secretion) and apical-to-basolateral (absorption) directions. Absorption of [3H]MPP+ at the apical membrane seems to occur through a carrier-mediated mechanism belonging to the Amphiphilic Solute Facilitator (ASF) family of transporters, but distinct from the known members of this family.

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Section: Discussionmentioning

confidence: 99%

Characterization of the transport of the organic cation [ 3 H]MPP + in human intestinal epithelial (Caco-2) cells

Martel

Calhau

Azevedo

2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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“…111-i ***~~~~~~~~~~~~~~~~1 (Sokol & McKinney, 1990;Saito et al, 1992;Saitoh et al, 1992). Moreover, it has recently been shown that the renal organic cation-H+ exchanger and P-glycoprotein can be photoaffinity labelled by the same substrate (Holohan et al, 1992 (Holohan et al, 1990).…”

Section: Resultsmentioning

confidence: 99%

Transport of celiprolol across human intestinal epithelial (Caco‐2) cells: mediation of secretion by multiple transporters including P‐glycoprotein

Karlsson

Kuo²,

Ziemniak³

et al. 1993

British J Pharmacology

170

100

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1 The transepithelial transport of the P-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2.2 The basal-to-apical transport (secretion) of ['4C]-celiprolol (50 jLM) was 5 times higher than apical-tobasal transport (absorption). In the presence of an excess (5 mM) of unlabelled celiprolol the basal-toapical transport was reduced by more than 80%, whereas the apical-to-basal transport remained unchanged. 3 Net celiprolol secretion obtained in the concentration range 0.01 to 5 mM displayed saturable kinetics with an apparent Km of 1.00 ± 0.23 mm and Vm,, of 113 ± 11 pmol/106 cells min-'. These results are consistent with saturable active secretion and provide an explanation for the dose-dependent bioavailability of celiprolol. 4 The secretion of celiprolol was sensitive to pH, and decreased in the absence of sodium and in the presence of ouabain, suggesting that transport was coupled to proton and sodium gradients. 5 The secretion of celiprolol was inhibited by substrates for P-glycoprotein (vinblastine, verapamil and nifedipine) and either inhibited or stimulated by typical substrates for the renal organic cation-H+ exchanger (cimetidine, N'-methylnicotinamide, tetraethylammonium and choline), suggesting that there are at least two distinct transport systems.6 The secretion of celiprolol was also inhibited by other P-adrenoceptor blocking drugs (acebutolol, atenolol, metoprolol, pafenolol and propranolol) and by the diuretics, acetazolamide, chlorthalidone and hydrochlorothiazide, suggesting that the clinically observed effect of chlorthalidone on the bioavailability of celiprolol occurs at the level of the intestinal epithelium.

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“…Our interest in these compounds was due to their potential degradation by hydrolytic enzymes. The hydrolysis products of long-chain alkanoylcholines, choline and fatty acids, are common human metabolites, and their metabolic pathways have been well investigated (13,18).…”

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confidence: 99%

Long-chain alkanoylcholines, a new category of soft antimicrobial agents that are enzymatically degradable

Ahlström

Chelminska-Bertilsson

Thompson

et al. 1995

Antimicrob Agents Chemother

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A new category of amphiphilic hydrolyzable quaternary ammonium compounds with rapid and high levels of antimicrobial activity was studied. The compounds, alkanoylcholines with hydrocarbon chains of 10 to 14 carbon atoms, are hydrolyzed by butyrylcholine esterase, which is present in human serum and mucosal membranes. The hydrolysis products are common components of human metabolism. Alkanoylcholines were tested and found to be active against gram-negative and gram-positive bacteria as well as yeasts. The microbicidal activities of the alkanoylcholines were comparable to the activities of the stable quaternary ammonium compounds of corresponding chain length and increased with an increasing number of carbon atoms. The compounds were also found to be hydrolyzed by enzymes present in certain microorganisms. The degradation was achieved after reaching the microbicidal effect.

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Carrier-mediated transport system for choline and its related quaternary ammonium compounds on rat intestinal brush-border membrane

Cited by 38 publications

References 31 publications

Characterization of the transport of the organic cation [ 3 H]MPP + in human intestinal epithelial (Caco-2) cells

Characterization of the transport of the organic cation [ 3 H]MPP + in human intestinal epithelial (Caco-2) cells

Transport of celiprolol across human intestinal epithelial (Caco‐2) cells: mediation of secretion by multiple transporters including P‐glycoprotein

Long-chain alkanoylcholines, a new category of soft antimicrobial agents that are enzymatically degradable

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