Solubility of long-chain fatty acids in phosphate buffer at pH 7.4

Vorum, Henrik; Brodersen, Rolf; Kragh‐Hansen, Ulrich; Pedersen, Anders Overgaard

doi:10.1016/0005-2760(92)90283-2

Cited by 134 publications

(80 citation statements)

References 17 publications

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“…This upward shift is similar to that found for fatty acids (FAs) and other weak lipophilic acids (18). Sulfonylurea derivatives are amphiphilic molecules and have limited solubility in pH 7.4 HEPES buffer (19) and, in the presence of SUVs, become incorporated into the phospholipid bilayer structure. Additional evidence for the incorporation of tolbutamide in the phospholipid bilayer comes from the differences in chemical-shift values of the phenyl-ring hydrogens at most pH values (Fig.…”

Section: Resultssupporting

confidence: 78%

Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism

et al. 2003

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Because sulfonylureas directly activate the exocytotic machinery, we were interested in the extent to which these compounds penetrate the ␤-cell plasma membrane and the underlying molecular mechanism(s). We now provide evidence that sulfonylureas cross phospholipid bilayer membranes rapidly and effectively by a free-diffusion mechanism. Two sulfonylurea compounds investigated by 1 H nuclear magnetic resonance spectroscopy, glibenclamide and tolbutamide, were found to incorporate into phospholipid bilayers, with the ionizable sulfonamide exposed to the aqueous interface and its apparent dissociation constant (pK a ) increased to ϳ7.0. Diffusion of weak amphiphilic acids across membranes is associated with a measurable change in pH. Thus, by using a fluorescencebased pH assay, we could investigate the diffusion of sulfonylurea compounds across phospholipid bilayer membranes. A fluorescent pH indicator (pyranin or [2,7-bis (2-carboxyethyl)-5(6)-carboxyfluorescein] [BCECF]) was trapped in egg phosphatidylcholine vesicles. Addition of glibenclamide decreased internal pH (pH in ), and addition of albumin reversed this drop by 50%. With the same amount of tolbutamide, the decrease in pH in was much smaller, primarily because of the lower partitioning of tolbutamide into phospholipid bilayers. Using similar protocols, we also demonstrated diffusion by the same mechanism across the ␤-cell plasma membrane. Thus, we now provide a molecular mechanism by which sulfonylureas can penetrate the plasma membrane and reach intracellular sites regulating exocytosis. Diabetes 52:2526 -2531, 2003 S ulfonylureas are drugs that stimulate secretion of insulin from the pancreatic ␤-cells (1,2) and are therefore used extensively in the treatment of type 2 diabetes. It is well established that sulfonylureas stimulate insulin release by interacting with the high-affinity 140-kDa SUR1 protein of the ATP-regulated K ϩ channel at the cytoplasmic leaflet of the plasma membrane. This interaction closes the channel, causing membrane depolarization, the opening of voltage-gated L-type Ca 2ϩ channels, an increase in cytoplasmic-free Ca 2ϩ concentration, and the activation of the secretory machinery (3,4). We have also shown that sulfonylureas stimulate insulin exocytosis by directly interacting with the secretory machinery and not through closure of the plasma membrane ATP-regulated K ϩ channel (5-7). This effect may constitute part of the therapeutic benefits of sulfonylureas and contribute to their hypoglycemic action in diabetes. Although this direct effect of sulfonylureas on insulin exocytosis is now well established and suggestions for underlying molecular mechanisms have been put forward (8), the physiological relevance of these findings are still in question. This skepticism originates primarily from the difficulty in envisaging how the sulfonylureas bypass the ␤-cell plasma membrane rapidly and effectively, thereby interacting with intracellular binding sites involved in the regulation of exocytosis. Indeed, earlier studies suggested that ...

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Section: Resultssupporting

confidence: 78%

Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism

et al. 2003

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“…Lipids may exist at low levels free in the cytosol, but non-esterifi ed fatty acid concentrations in adipocytes are many fold higher [4] than in vitro solubility measurements would suggest possible [22]. Fatty acids may additionally equilibrate within the plasma membrane, various organelle membranes, or the surface of the triglyceride droplet, but elevated levels will exert a disruptive micellar effect on membranes and proteins.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and biophysical analysis of the intracellular lipid binding proteins of adipocytes

Simpson

LiCata

Coe

et al. 1999

Lipid Binding Proteins Within Molecular and Cellular Biochemistry

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“…The solubility of oil, fat and fatty acids in water would be an important and basic parameter. However, there are only a few reports on such solubility at temperatures lower than 609 C. [12][13][14] In this context, we measured the solubility of fatty acids with even carbon numbers of 8 to 18 in water at 609 C to 2309 C under pressures of 5 and 15 MPa.…”

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confidence: 99%

Solubility of Saturated Fatty Acids in Water at Elevated Temperatures

Khuwijitjaru

Adachi

Matsuno

2002

Bioscience, Biotechnology, and Biochemistry

108

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The solubility in water of saturated fatty acids with even carbon numbers from 8 to 18 was measured in the temperature range of 60 to 2309 C and at a pressure of 5 or 15 MPa. The pressure had no signiˆcant eŠect on the solubility. The solubility of the fatty acids increased with increasing temperature. At temperatures higher than about 1609 C, the logarithm of the solubility in mole fraction was linearly related to the reciprocal of the absolute temperature for each fatty acid, indicating that the water containing solubilized fatty acid molecules formed a regular solution at the higher temperatures. The enthalpy of a solution of the fatty acids in water, which was evaluated from the linear relationship at the given temperatures, increased linearly with the carbon number of the fatty acid

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Solubility of long-chain fatty acids in phosphate buffer at pH 7.4

Cited by 134 publications

References 17 publications

Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism

Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism

Biochemical and biophysical analysis of the intracellular lipid binding proteins of adipocytes

Solubility of Saturated Fatty Acids in Water at Elevated Temperatures

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