Effects of adriamycin on lipid polymorphism in cardiolipin-containing model and mitochondrial membranes.
The effects of the anti-tumor drug adriamycin on lipid polymorphism in cardiolipin-containing model membranes and in isolated inner mitochondrial membranes has been examined by 31P-NMR. Adriamycin binding does not affect the macroscopic structure or local order in the phosphate region of cardiolipin liposomes. In cardiolipin liposomes and in cardiolipin-phosphatidylcholine (1:1) liposomes, the drug inhibits the ability of Ca2+ to induce the hexagonal HII phase. Adriamycin interaction with both dioleoylphosphatidylethanolamine-cardiolipin (2:1) and dioleoylphosphatidylethanolamine-phosphatidylserine (1:1) liposomes results in structural phase separation into a liquid-crystalline hexagonal HII phase for the phosphatidylethanolamine and a liquid-crystalline lamellar phase for the negatively charged phospholipid. Combined high-resolution 31P-NMR, electron microscopy and light scattering studies reveal the prominent fusion capacity of adriamycin towards cardiolipin-phosphatidylcholine small unilamellar vesicles. Addition of Ca2+ to total rat liver inner mitochondrial membrane lipids, dispersed in excess buffer, results in hexagonal HII formation for part of the phospholipids. By contrast, the original bilayer structure is completely conserved when the above experiment is performed in the presence of adriamycin. 31P-NMR spectra of isolated inner mitochondrial membranes are indicative of a bilayer organization for the majority of the phospholipids. Approximately 15% of the signal intensity originates from phospholipids which experience isotropic motion. Adriamycin addition almost completely eliminates the latter spectral component. In the absence of adriamycin, Ca2+ addition greatly increases the percentage of the phospholipids giving rise to an isotropic signal possibly indicating the formation of non-lamellar lipid structures. Adriamycin which specifically binds to cardiolipin (K. Nicolay et al. (1984) Biochim. Biophys. Acta 778, 359-371) completely blocks the Ca2+-induced structural reorganization of the lipids in this membrane.
D002118:Calcium / Q000378:metabolism; D002308:Cardiolipins / Q000502:physiology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004317:Doxorubicin / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects; D008051:Lipid Bilayers; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D008954:Models, Biological; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines
D002308:Cardiolipins; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D004317:Doxorubicin; D002118:Calcium