Effect of FK 506 and Cyclosporins on Model Membranes Studied by Nuclear Magnetic Resonance Spectroscopy

Rossaro, Lorenzo; Dowd, Susan R.; Simplăceanu, Virgil; Naccarato, R.; Thiel, David H. Van; Ho, Chien

doi:10.1007/978-94-011-1994-8_29

Cited by 2 publications

(4 citation statements)

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“…However, previous results reported by both our team and other authors suggest that cyclosporin A also induces other alterations in hepatocyte functions. 1988) and reduces membrane fluidity (Rossaro et at. 1991;Moseley et at.…”

Section: Discussionmentioning

confidence: 99%

“…Its therapeutic use is, however, often limited by its side effects, which include renal and hepatic dysfunction (Kahan 1989;Lorber et al 1987;Thomas & Gordon 1986;Wiesner et al 1990). Indeed, cyclosporin A-induced cholestasis and hyperbilirubinaemia are related to an inhibition of the hepatic uptake of bile acids and bilirubin Kenny et al 1986;Kukonguiriyapan & Stacey 1988;Moseley et al 1990;Nassuato et al 1988;Rotolo et al 1986), resulting from changes in the physicochemical characteristics of liver plasma membranes, membrane fluidity (Farthing & Clark 1981;Rossaro et al 1991;Whitington et al 1988) and/ or Na+/K+-ATPase activity (Stone et al 1987;Thomas & Gordon 1986). Indeed, cyclosporin A-induced cholestasis and hyperbilirubinaemia are related to an inhibition of the hepatic uptake of bile acids and bilirubin Kenny et al 1986;Kukonguiriyapan & Stacey 1988;Moseley et al 1990;Nassuato et al 1988;Rotolo et al 1986), resulting from changes in the physicochemical characteristics of liver plasma membranes, membrane fluidity (Farthing & Clark 1981;Rossaro et al 1991;Whitington et al 1988) and/ or Na+/K+-ATPase activity (Stone et al 1987;Thomas & Gordon 1986).…”

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confidence: 99%

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Cyclosporin A-Induced Cholestasis in the Rat

et al. 1992

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Cyc1osporin A, a powerful immunosuppressor drug, induces nephrotoxicity and hepatotoxicity. The purpose of this study was to evaluate the ability of S-adenosyl-L-methionine (SAMe) to antagonise the cyc1osporin A-induced hepatotoxicity in rats treated with cyc1osporin A plus SAMe. Cyc1osporin A treatment for I or 2 weeks increases plasma bilirubin, alters some plasma biochemical indicators of hepatic and renal function, causes cholestasis and reduces the biliary concentration and secretion of bile acid and other bile components. SAMe pretreatment and simultaneous treatment with SAMe plus cyc1osporin A suppresses bilirubin increases in plasma, attenuates cholestasis and totally antagonises the adverse effects of cyc1osporin A on bile acid secretion. Although cyc1osporin A-induced hepatotoxicity in the rat is a multifactorial phenomenon, we suggest that the hepatoprotective effects of SAMe against cyc1osporin A could be related to its regulatory function of membrane lipid composition and fluidity, either alone or combined with stimulation of the hepatic synthesis of thiol compounds.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cyclosporin A-Induced Cholestasis in the Rat

et al. 1992

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“…With the same technique, Schote and co-workers suggested that CsA could be incorporated into liposomal membranes with an upper limit of one molecule associated with nine phospholipid molecules . Moreover, cholesterol is able to inhibit the interaction of CsA with model membranes. , Other studies also suggested that CsA induces the aggregation of lecithin liposomes and decreases the size of liposomes as observed by electron microscopy. , In addition, Fahr and co-workers showed that CsA can bind to model membranes, which modifies their permeability to ions …”

Section: Introductionmentioning

confidence: 98%

“…13,16 Other studies also suggested that CsA induces the aggregation of lecithin liposomes and decreases the size of liposomes as observed by electron microscopy. 17,18 In addition, Fahr and co-workers showed that CsA can bind to model membranes, which modifies their permeability to ions. 19 We have recently shown a marked preference of CsA with respect to its insertion into SM monolayers, but we did not assess the membranolytic activity of CsA.…”

Section: ' Introductionmentioning

confidence: 99%

The Potent Antimalarial Peptide Cyclosporin A Induces the Aggregation and Permeabilization of Sphingomyelin-Rich Membranes

2011

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Cyclosporin A (CsA) is a hydrophobic peptide drug produced by the fungus Tolypocladium inflatum. CsA is commonly used as an immunosuppressive drug, but it also has antimalarial activity. The immunosuppressive activity of CsA is clearly due to its association with specific proteins of immune cells such as cyclophilins. By contrast, the antimalarial properties of this peptide are completely independent of the association with a parasite's cyclophilins. Because of its hydrophobicity, CsA may interact with biological membranes, which may participate in its therapeutic effect. Recently, we have shown a marked preference of CsA for insertion into sphingomyelin (SM) monolayers. In this article, we measure for the first time the ability of CsA to induce permeabilization and aggregation and to change the lipid order, especially in the presence of SM. Calcein-release experiments permitted us to show that CsA causes the leakage of the fluorescent probe from SM-rich liposomes by 40% and PC liposomes by 11%, suggesting a lipid-selective effect. Electron microscopy and dynamic light scattering experiments confirmed the different interaction of CsA with SM and PC vesicles: it formed much larger aggregates with SM than with PC. Our results taken together suggest that CsA could specifically weaken and aggregate SM-rich membranes, which could in turn explain why CsA is efficient in the treatment of malaria. Indeed, CsA could inhibit the development of Plasmodium by permeabilizing and aggregating the SM-rich membrane network formed by the parasite during its intraerythrocytic growth cycle.

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Effect of FK 506 and Cyclosporins on Model Membranes Studied by Nuclear Magnetic Resonance Spectroscopy

Cited by 2 publications

References 25 publications

Cyclosporin A-Induced Cholestasis in the Rat

Cyclosporin A-Induced Cholestasis in the Rat

The Potent Antimalarial Peptide Cyclosporin A Induces the Aggregation and Permeabilization of Sphingomyelin-Rich Membranes

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