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PubMed2003

Adult onset Niemann-Pick type C disease: A clinical, neuroimaging and molecular genetic study.

We report on a patient with adult-onset Niemann-Pick type C (NPC) disease, carrying the mutations P1007 and I1061T in the NPC1 gene, presenting with marked psychiatric changes followed by dystonia and cognitive impairment. Filipin staining, single photon emission computed tomography perfusional, positron emission tomography metabolic, conventional magnetic resonance imaging, and magnetic resonance spectroscopy findings suggested a pathophysiological correlation with phenotype expression. This case expands the clinical and genetic spectrum of the rare adult-onset NPC disease phenotype.

Adult↗
PubMed2003

Spatial and temporal distribution of intracellular free cholesterol in brains of a Niemann-Pick type C mouse model showing hyperphosphorylated tau protein. Implications for Alzheimer's disease.

Niemann-Pick type C (NPC) disease is a fatal hereditary neurovisceral disorder with diagnostically relevant intracellular accumulation of cholesterol in non-brain tissue, for example the spleen and fibroblasts. In the brain, many ballooned neurons are seen. Using filipin microfluorodensitometry, significant accumulations of free cholesterol in specified neurons have been described in NPC patients. The present study demonstrates spatial and temporal accumulation of free cholesterol in the brains of homozygous NPC (-(npc)/-(npc)) mice, a widely acknowledged mouse model, and in primarily cultured neurons therefrom. Intraneuronal storage of free cholesterol was already prominent at a pre-clinical stage in various grey matter areas of the murine cerebral cortex. Hippocampal areas showed differential development of the pathological distribution of free cholesterol. The pyramidal cells in the CA3 sector of Ammon's horn were affected much earlier than in CA1. Some of the deeper cerebral nuclei were affected only slightly, even at the final stage. Neurons (E15-E17) cultured in a cholesterol-free medium also showed massive accumulation of intracellular free cholesterol. In addition, brains from the murine NPC model for Alzheimer's disease (AD)-like changes in the microtubule-associated protein tau were tested using the Gallyas silver technique and AT8-immunolabelling, since both human diseases are accompanied by intraneuronal tangles made up of tau protein aggregations. Although the analysis failed to show classical silver-stainable tangles of the AD type in the NPC mice, tau protein phosphorylated at epitopes considered to represent early stages of AD was found. This further strengthens the concept that an alteration in cholesterol metabolism may play an important role in AD. The NPC mouse model may thus serve as a tool to analyse the role of cholesterol in initial changes of tau that eventually lead to the formation of tangles in both NPC and AD.

Alzheimer Disease↗
PubMed1995

Mitochondrial calcium uptake stimulated by Cibacron blue F3GA in bovine sperm.

The triazine dye Cibacron Blue F3GA stimulated calcium uptake into an ionomycin-sensitive compartment of washed bovine sperm. Cibacron blue-stimulated uptake was not sensitive to nifedipine, diltiazem, or verapamil, but was blocked by transition metals, 1 microM ruthenium red, rotenone, and the protonophore CCCP. Uptake was dependent on the maintenance of energized mitochondria but not on oxidative or substrate level ATP production and was not supported by glycolysis. The cibarcon blue-stimulated uptake was judged by these criteria to be mitochondrial. Uptake in the absence of Cibacron blue was 0.046 +/- 0.008 and 0.268 +/- 0.068 nmol/min/10(8) cells with 0.1 mM Cibacron blue at 15 microM Ca2+. Half-maximal stimulation occurred at 20-25 microM Cibacron blue. Cibacron blue also allowed efflux of mitochondrial calcium in the presence of external calcium. This efflux would be blocked by ruthenium red, Ni2+, and La3+, but not by Co2+, which effectively blocked Cibacron blue-stimulated influx. Permeabilizing the plasma membrane with filipin indicated that Cibacron blue stimulation of mitochondrial calcium uptake operates directly on the mitochondria. Cibacron blue does not stimulate mitochondrial respiration and thus, calcium uptake was not the result of increased mitochondrial flux.

Adenosine Triphosphate↗
PubMed2001

Galectin-3 mediates the endocytosis of beta-1 integrins by breast carcinoma cells.

Galectin-3, a beta-galactoside binding lectin, has been demonstrated to play a key role(s) in cell to extracellular matrix interaction. The precise mechanism by which it modulates cellular adhesion is presently unclear and warrants further studies. We hereby report that galectin-3 mediates the endocytosis of beta-1 integrins in a lactose-dependent manner. Interestingly we observed that galectin-3 was also rapidly internalized by the cells via the same pathway and the internalization was completely blocked by lactose. The endocytosis process was temperature dependent and was inhibited by filipin but not chlorpromazine. The endocytosis of galectin-3 and beta-1 integrins by the cells was accompanied by rapid cell spreading due to cytoskeletal reorganization. The data suggest a novel mechanism by which galectin-3 and beta-1 integrins are internalized into breast carcinoma cells via a cavaleolae-like pathway of endocytosis.

Actin Cytoskeleton↗
PubMed2000

NPC1-containing compartment of human granulosa-lutein cells: a role in the intracellular trafficking of cholesterol supporting steroidogenesis.

Steroidogenic cells represent unique systems for the exploration of intracellular cholesterol trafficking. We employed cytochemical and biochemical methods to explore the expression, regulation, and function of the Niemann-Pick C1 protein (NPC1) in human granulosa-lutein cells. NPC1 was localized in a subset of lysosome-associated membrane glycoprotein 2 (LAMP-2)-positive vesicles. By analyzing the sensitivity of NPC1 N-linked oligosaccharide chains to glycosidases and neuraminidase, evidence was obtained for movement of nascent NPC1 from the endoplasmic reticulum through the medial and trans compartments of the Golgi apparatus prior to its appearance in cytoplasmic vesicles. NPC1 protein content and the morphology and cellular distribution of NPC1-containing vesicles were not affected by treatment of the granulosa-lutein cells with 8-Br-cAMP, which stimulates cholesterol metabolism into progesterone. In contrast, steroidogenic acute regulatory (StAR) protein levels were increased by 8-Br-cAMP. Incubation of granulosa-lutein cells with low-density lipoprotein (LDL) in the presence of the hydrophobic amine, U18666A, caused accumulation of free cholesterol in granules, identified by filipin staining, that contained LAMP-2 and NPC1. These granules also stained for neutral lipid with Nile red, reflecting accumulation of LDL-derived cholesterol esters. LDL-stimulated progesterone synthesis was completely blocked by U18666A, leaving steroid output at levels similar to those of cells incubated in the absence of LDL. The hydrophobic amine also blocked the LDL augmentation of 8-Br-cAMP-stimulated progesterone synthesis, reducing steroid production to levels seen in cells stimulated with 8-Br-cAMP in the absence of LDL. Steroidogenesis recovered after U18666A was removed from the culture medium. U18666A treatment caused a 2-fold or more increase in NPC1 protein and mRNA levels, suggesting that disruption of NPC1's function activates a compensatory mechanism resulting in increased NPC1 synthesis. We conclude that the NPC1 compartment plays an important role in the trafficking of LDL-derived substrate in steroidogenic cells; that NPC1 expression is up-regulated when NPC1 action is blocked; and that the NPC1 compartment can be functionally separated from other intracellular pathways contributing substrate for steroidogenesis.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Complementation studies in human and feline Niemann-Pick type C disease.

Complementation studies were performed to determine if the gene responsible for the major form of human Niemann-Pick type C disease (NPC) and a feline model of NPC are orthologous. Cell fusions between human NPC and feline NPC fibroblasts were conducted to assess whether the multinucleated heterokaryons that were formed showed a reversal of the NPC phenotype. Cultured fibroblasts from NPC-affected humans and NPC-affected cats were hybridized and then analyzed for complementation by challenging the cells with low-density lipoprotein (LDL) and subsequently staining with the fluorescent antibiotic filipin to visualize any abnormal accumulation of unesterified cholesterol. All of the multinucleated cells formed from these fusions retained the NPC staining phenotype, indicating an absence of complementation and suggesting that the underlying defect in the major form of human NPC and this feline model of NPC involve orthologous genes.

Animals↗
PubMed2001

Evidence of transcellular permeability pathway in microvessels.

We used video fluorescence microscopy of the vascular bed in the cremaster muscle of rat and mouse to study the transfer of plasmalemma vesicles (caveolae) across the microvessel barrier in situ. The water-soluble styryl pyridinium dye RH414, which adsorbs to and fluoresces at the membrane-water interface, was used as a marker for vesicular traffic through endothelial cells. Fluorescein isothiocyanate (FITC), similar in molecular size to the styryl pyridinium probe, was used to mark for dye transfer by the paracellular pathway. Transcellular dye flux was determined by comparing the fluorescence intensities of RH414 and FITC on either side of the vessel wall (i.e., in microvessel lumen and in muscle tissue at various distances from the microvessel wall). We observed that RH414 accumulated in the interstitium more rapidly than FITC. We next studied the role of the 60-kDa albumin-binding glycoprotein gp60, hypothesized to activate transcellular permeability, in stimulating the transcellular vesicle traffic. Introduction of anti-gp60 antibody into the microvessel to cross-link and activate gp60 markedly increased the transvascular flux of RH414. Control isotype-matched antibody had no effect on the RH414 flux. The sterol-binding agent filipin, which disassembles caveolae, inhibited the RH414 flux induced by gp60 cross-linking. The transfer of styryl pyridinium dyes in intact microvessels suggests that plasmalemmal membrane traffic across the skeletal muscle microvessel barrier is a constitutively active process. The results indicate that the gp60-dependent pathway is important in regulating endothelial permeability in situ via a transcellular mechanism.

Animals↗
PubMed1991

Structural features of the lateral walls in mammalian cochlear outer hair cells.

Freeze-fracture, freeze-etching and thin sections have been used to determine features of the structural organisation of the lateral walls in cochlear outer hair cells. The presence of an organised meshwork of filaments in the lateral cortex of the cell is confirmed in intact unfixed cells. This meshwork showed morphological features similar to the cytoskeletal lattice. The lateral plasma membrane is shown to be protein-rich and to contain cholesterol. The membranes of the subplasmalemmal lateral cisternae contain much less protein, and little cholesterol as judged by their responses to filipin and tomatin. These findings indicate differences in the physical properties of the two membrane systems. On the fracture faces of the plasma membrane there is a high density of intramembrane particles and this particle population is heterogeneous. Some particles show morphological features consistent with those of transmembrane channels. Regularly spaced pillars crossing the space between the plasma and cisternal membranes were identified both in thin sections and in freeze-etched preparations, but neither the plasma nor cisternal membrane fracture faces showed any feature corresponding directly to the pillar. This suggests the pillars do not insert directly into either membrane. Freeze-fracture and freeze-etching of unfixed cells indicated that the pillar is indirectly associated with the cytoplasmic surface of the plasma membrane, and, at its inner end, linked to the cortical cytoskeletal lattice on the outer surface of the cisternal membrane.

Animals↗
PubMed1986

Proton pump activity and Mg-ATPase activity in rat kidney cortex brushborder membranes: effect of 'proton ATPase' inhibitors.

In order to further characterize the ATP driven proton pump present in the luminal membrane of the renal proximal tubule, brushborder membranes were isolated from rat kidney cortex and the effect of various proton ATPase inhibitors on intravesicular ATP hydrolysis in sealed brushborder membrane vesicles and on Mg-ATPase activity in permeabilized brushborder membranes was investigated. The protonophor induced intravesicular ATP hydrolysis (ATP driven proton pump) was inhibited by DCCD and filipin but not by diethylstilbestrol and duramycin. All four compounds decreased Mg-ATPase activity, the two former inhibited the ATPase activity with a lower potency than the proton pump. NEM--up to 10 mM--and orthovanadate did not affect intravesicular ATP hydrolysis nor Mg-ATPase activity. From the relative sensitivity of the proton pump and the Mg-ATPase activity to the inhibitors it is concluded that about 35% of the Mg-ATPase activity found in the brushborder membrane can be attributed to the ATP-driven proton pump. Furthermore, the results obtained with NEM and duramycin suggest that the brushborder membrane proton pump has different properties than the proton pump in clathrin-coated vesicles or endosomes. The results presented above raise the possibility that the brushborder membrane proton pump is predominantly involved in acid secretion by the proximal convoluted tubule whereas the proton pump in clathrin-coated vesicles may be predominantly involved in the endocytosis of larger peptides and proteins.

Animals↗
PubMed1996

Co-cultivation of Niemann-Pick disease type C fibroblasts belonging to complementation groups alpha and beta stimulates LDL-derived cholesterol esterification.

Niemann-Pick disease type C (NPC) is a neurovisceral storage disorder with an unknown primary deficiency. Somatic cell hybridization experiments using human cultured fibroblasts have shown that two complementation groups (NPC-alpha and NPC-beta) are associated with the biochemical and clinical phenotypes comprising NPC. We identified the rarer complementation group NPC-beta originally using the technique of filipin staining as a marker for complementation. In this study we show that the esterification of cholesterol derived from the LDL pathway can be used as an isotopic assay. However, multinuclear hybrids exhibit a delayed induction in this pathway. Furthermore, we discovered that, in the presence of an LDL source, co-cultivation of fibroblasts belonging to NPC-alpha and NPC-beta stimulated cholesterol esterification.

Cholesterol↗
PubMed1989

Correction of sphingomyelinase deficiency in Niemann-Pick type C fibroblasts by removal of lipoprotein fraction from culture media.

The average sphingomyelinase activity of fibroblasts obtained from 12 Niemann-Pick type C patients was 37.9% of that of normal fibroblasts (27.2 versus 72 nmol (mg protein)-1 h-1) when the cells were cultured in minimum essential medium containing 13% fetal bovine serum. Following replacement of the above medium with medium in which the lipoprotein fraction had been removed from the fetal bovine serum, the sphingomyelinase activity rose over a 7-day period from about 1/3 of normal to normal or above. Upon reintroduction of medium containing 10% fetal bovine serum which had not been extracted, the sphingomyelinase activity of the Niemann-Pick type C cells again fell within 48 h to 30% of the normal controls. In contrast, cell lines from patients with either Niemann-Pick Type A or B were not influenced by the presence or the absence of lipoprotein, i.e. lacked sphingomyelinase activity under all culture conditions examined. Histochemical staining with filipin showed an inverse relationship between the sphingomyelinase activity and intracellular, free, unesterified, cholesterol level. Moreover, immunochemical staining with an antibody against a lysosomal membrane protein provided direct evidence that the accumulation of unesterified cholesterol in cells cultured in regular (non-extracted) medium occurred within lysosomes and/or related organelles.

Cells, Cultured↗
PubMed1982

An ATP-driven proton pump in brush-border membranes from rat renal cortex.

The rate of ATP hydrolysis in ATP-preloaded plasma membrane vesicles derived from the luminal membrane of renal cortical tubules, and the rate of H+ secretion out of the same vesicles were investigated. Both were inhibited at low temperature, by the action of filipin, an antibiotic that complexes with cholesterol in plasma membranes, and by the action of blockers of mitochondrial Fo hydrogen channels, dicyclohexylcarbodiimide and Dio-9. Valinomycin in the presence of K+ showed a stimulatory effect, the protonophor carbonyl-cyanid-p-trifluormethoxy-phenylhydrazone stimulated the intravesicular ATP hydrolysis and apparently abolished acidification of the extravesicular medium. Lowering of the pH of the extravesicular medium retarded ATP hydrolysis, while readjustment of extra- and intravesicular pH accelerated ATP hydrolysis again. These findings strongly support the assumption that an ATP-driven proton pump is located in the luminal membrane of renal cortical tubules.

Adenosine Triphosphatases↗
PubMed1979

Further evidence for the existence of an intrinsic bicarbonate-stimulated Mg2+-ATPase in brush border membranes isolated from rat kidney cortex.

The aim of this study was to provide further evidence for the existence of a nonmitochondrial becarbonate-stimulated Mg2+-ATPase in brush border membranes derived from rat kidney cortex. A plasma membrane fraction rich in brush border microvilli and a mitochondrial fraction were isolated by differential centrifugation. Both fractions contain a Mg2+-ATPase activity which can be stimulated by bicarbonate. The two Mg2+-ATPases are stimulated likewise by chloride, bicarbonate, and sulfite or inhibited by oligomycin and aurovertin, though to different degrees. In contrast to these similarities, only the Mg2+-ATPase activity of the mitochondrial fraction is inhibited by atractyloside, a substance which blocks an adenine nucleotide translocator in the inner mitochondrial membrane. On the other hand, filipin, an antibiotic that complexes with cholesterol in the membranes inhibits exclusively the Mg2+-ATPase of the cholesterol-rich brush border membranes. Furthermore it could be demonstrated by the use of bromotetramisole, an inhibitor of alkaline phosphatase activity, that the Mg2+-ATPase activity in the membrane fraction is not due to the presence of the highly active alkaline phosphatase in these membranes. These results support the assumption that an intrinsic bicarbonate-stimulated Mg2+-ATPase is present in rat kidney brush border membranes.

Adenosine Triphosphatases↗
PubMed1985

Primary culture of rat hepatocytes as a model system of canalicular development, biliary secretion, and intrahepatic cholestasis. V. Disturbance of the cellular membrane and bile canalicular ultrastructure induced by chlorpromazine.

In the present paper rat hepatocytes in primary monolayer culture were used to investigate the adverse effects of chlorpromazine (CPZ) at the cellular level. As revealed by thin sectioning many of the ultrastructural alterations were comparable to those described for the isolated perfused rat liver under the influence of CPZ. Alterations comprised short-term effects, such as dilation of the rough endoplasmic reticulum and the nuclear envelope, and long-term effects including huge accumulations of myeloid bodies within the cytoplasm as well as dilation and diverticulation of bile canaliculi. Freeze-fracturing revealed the dislocation of intramembrane particles in the sinusoidal plasma membrane which could be detected as early as 30 min after exposure to CPZ. As judged from filipin cytochemistry, alterations in the cholesterol content seems to play a minor role in the process of membrane damage except at the sinusoidal surface where a reduction of cholesterol content may contribute to the impairment of membrane functions. It is concluded that CPZ exerts its cholestatic effect primarily by a rapid disturbance of the membrane architecture of the sinusoidal surface and secondarily by other interactions with the bile secretory apparatus.

Animals↗
PubMed1975

Studies on tetrahymena membranes. Modification of surface membrane lipids by replacement of tetrahymanol by exogenous ergosterol in Tetrahymena pyriformis.

Tetrahymena pyriformis WH-14 cells were grown in the medium supplemented with ergosterol (1 mg/100 ml) and the effects of replacement of tetrahymanol by ergosterol upon the lipid composition in the surface membranes (cilia and pellicles) were examined. 1. By scanning and freeze-etch electron microscopy it was suggested that exogenous ergosterol would be inserted into the lipid regions in the surface membranes. Although freeze-etched faces of filipin-treated membranes containing the native tetrahymanol showed a random distribution of 85-a protein particles, the ergosterol-replaced membranes after the same polyene treatment revealed the marked ultrastructural alterations on the fracture faces. 2. The replacement of tetrahymanol in membranes by ergosterol induced a profound alteration in the phospholipid class composition and a marked increase in phosphatidylethanolamine with a compensatory decrease in phosphatidylcholine and 2-aminoethylphosphonolipid. 3. There are significant and quantitative but not qualitative changes in the fatty acid composition of total lipids from the ergosterol-replaced membranes. There are also increases in saturated and decreases in unsaturated fatty acids. Phosphatidylethanolamine acyl chains particularly become more saturated, as compared with two other phospholipids, in ergosterol-replaced pellicles. This increase in saturation is due to an appreciable increase in C14:0, C16:0 and iso-C17:0, and a decrease in C18:1(delta9), C18:2(delta9,12) and C18:3(delta6,9,12). 4. These results suggest that profound alterations in phospholipids as well as in their fatty acyl chains are required to modify the overall membrane lipid composition for the maintenance of proper membrane fluidity. Our data would also support the thesis that polat head groups are involved in the membrane lipid organization and that sterols interact selectively with phospholipid molecules containing the appropriate fatty acyl chain composition in biological membranes.

Acetates↗
PubMed1980

Effect of 1,25-dihydroxyvitamin D-3 on phosphate uptake into chick intestinal brush border membrane vesicles.

Brush border membrane vesicles prepared from the vitamin D-deficient chick duodenum take up phosphate and show an overshoot phenomenon in the presence of NaCl. Substitution of choline chloride for NaCl reduces phosphate uptake. Prior treatment of vitamin D-deficient chicks with 1,25-dihydroxy-vitamin D-3 increases the initial rate of Na+-dependent phosphate uptake into the brush border vesicles. This Na+-dependent phosphate uptake is a saturable process, exhibiting an apparent Km of 0.31 mM and a V of 385 pmol/mg per 15 s. Pretreatment of chicks with 1,25-dihydroxyvitamin D-3 leads to an increase in V (750 pmol/mg per 15 s) without significantly altering the apparent Km (0.33 mM). Addition of Ca2+, either in the presence or absence of the polyene antibiotic, filipin, or of calmodulin, has no effect on Na+-dependent phosphate uptake. Pretreatment of the vitamin D-deficient chick with a dose of cycloheximide sufficient to inhibit membrane protein synthesis blocks the 1,25-dihydroxyvitamin D-3-induced increase in alkaline phosphatase activity, but does not affect the stimulation of Na+-dependent phosphate uptake. From these data, it is concluded that 1,25-dihydroxyvitamin D-3 stimulates Na+-dependent phosphate transport at the brush border membrane of the enterocyte, that alkaline phosphatase is not directly involved in this process, and that this effect of 1,25-dihydroxyvitamin D-3 is independent of new protein synthesis.

Alkaline Phosphatase↗
PubMed1980

The action of pimaricin, etruscomycin and amphotericin B on liposomes with varying sterol content.

1. The effect of pimaricin, etruscomycin and amphotericin B on the K+ release from liposomes is strongly dependent on their sterol concentration. Pimaricin and etruscomycin induce K+ release from egg lecithin liposomes with cholesterol contents of more than 25 and 10 mol%, respectively, at polyene concentrations of 100 and 10 microgram/ml, respectively. Amphotericin B shows a maximal effect at a cholesterol content of 20 mol% at a concentration of 0.4 microgram/ml. 2. For liposomes containing ergosterol the sensitivity is shifted to a lower sterol content. All three polyenes show activity at 10 mol% ergosterol. The sensitivity for amphothericin B is increased approx. 15 times by the incorporation of ergosterol compared to cholesterol. The increase in sensitivity is much less for pimaricin and etruscomycin. The K+ release is maximal at an ergosterol concentration of 30 mol%. 3. Pimaricin, etruscomycin and amphotericin B can induce K+ release from erythrocytes without the release of haemoglobin at concentrations of 20, 2 and 1 microgram/ml, respectively. For these polyenes a selective permeability change is also demonstrated for liposomes since K+ is released but no [14C]dextran. Filipin shows a nonselective release of solutes from erythrocytes and liposomes. 4. At cholesterol concentrations higher than 20 mol% and ergosterol concentrations higher than 10 mol%, etruscomycin, pimaricin and amphotericin B show little dependence of the bilayer thickness and are able to release K+ from didocosenoyl phosphatidylcholine liposomes after addition of the polyene to one side of the membrane. A possible mechanism is discussed.

Amphotericin B↗
PubMed1985

Interaction of the polyene antibiotic etruscomycin with large unilamellar lipid vesicles: binding and proton permeability inducement.

The effect of the polyene antibiotic etruscomycin on the permeability of large unilamellar lipid vesicles was investigated. Proton leakage was induced in egg-yolk phosphatidylcholine (EPC) vesicles only when sterol was present in the membrane; the extent of leakage was limited. High etruscomycin/lipid ratios (R) were necessary (R greater than 0.1). Higher percentages of sterol increased the permeability, slightly more strongly for ergosterol than for cholesterol. Dipalmitoylphosphatidylcholine (DPPC) vesicles were more sensitive to permeability inducement, even in the absence of sterol in the bilayer (inducement for R greater than 0.06). The interactions of etruscomycin with the vesicles were examined by circular dichroism, fluorescence and 31P-NMR. In the range of antibiotic concentration where permeability was induced, R greater than 0.1 for EPC vesicles, R greater than 0.06 for DPPC vesicles, etruscomycin exhibited characteristic circular dichroism spectra independent of the presence of sterol. Under the same conditions, 31P-NMR and fluorescence studies indicated a destruction or a fusion of the vesicle bilayer. At lower etruscomycin concentrations (R less than 0.03), the etruscomycin circular dichroism spectra were different, indicating that the interaction with membranes containing ergosterol differed from that with membranes containing cholesterol. From correlating the increase in fluorescence intensity with this interaction, as well as from exchange experiments, it was inferred that etruscomycin at a low antibiotic/lipid ratio is more strongly bound to ergosterol-containing vesicles than to cholesterol-containing vesicles. These results and their comparison with the results obtained with other polyene antibiotics indicate that at low R etruscomycin resembles amphotericin rather than filipin in its preferential binding to ergosterol-containing vesicles. At higher R, that is in conditions where permeability is induced, the selectivity is different. The corresponding mechanism seems not to involve the formation of an etruscomycin-sterol channel, since the hydrophobic chain of the complex would be too short to form a channel.

Antifungal Agents↗