Interactions of amiodarone with model membranes and amiodarone-photoinduced peroxidation of lipids.
The potent antiarrhythmic drug, amiodarone (AMIO) exhibits phototoxicity, which is thought to be related to its interaction with biological membranes. We report here a spectroscopic study of the interactions of this drug with phosphatidylglycerol (PG) and phosphatidylcholine (PC) liposomes used as membrane model systems. A linear increase in absorbance at 300 nm was observed with increasing addition of AMIO to dimyristoyl-DL-PC (DMPC) liposomes over all the drugs-lipid molar ratio (Ri)s tested. In contrast, in the dimyristoyl-DL-PG (DMPG) liposomes, there was a dramatic increase in absorbance at values of Ri above unity. Light scattering by DMPG liposomes at 350 nm increased with increasing AMIO concentration up to a Ri = 1, and then decreased with increasing drug concentration. Such changes were not observed with the DMPC liposomes. Moreover, addition of AMIO changed the fluorescence polarization rate of 1,6-diphenyl 1,3,5-hexatriene embedded in these liposomes. It reduced the rate below the phase transition temperature (Tt) of the lipid, but increased it above this temperature. These effects on the lipidic phases observed at low Ri were more pronounced on the DMPG than on the DMPC liposomes. The strong interactions of AMIO with phospholipids, especially the acidic ones, were confirmed by liposome size determinations. All these data strongly suggest that the drug was incorporated in the core of the lipid bilayers. Such a penetration would favor a drug-photoinduced peroxidation of lipids. Indeed, UV irradiation of AMIO-DOPG mixtures led to the disappearance of the unsaturated fatty acids of phospholipids, checked by gas chromatography measurements, which was correlated with the amount of oxygen consumed. This showed that AMIO did photosensitize phospholipid peroxidation.
Sautereau
A M
AM
Centre de Recherche de Biochimie et de Génétique Cellulaires, LP du CNRS, Toulouse, France.
Tournaire
C
C
Suares
M
M
Tocanne
J F
JF
Paillous
N
N
D000638:Amiodarone / Q000378:metabolism / Q000494:pharmacology*; D002849:Chromatography, Gas; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D005454:Fluorescence Polarization; D008051:Lipid Bilayers; D015227:Lipid Peroxidation / Q000187:drug effects*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D010101:Oxygen Consumption; D010715:Phosphatidylglycerols / Q000737:chemistry; D010743:Phospholipids / Q000032:analysis; D010777:Photochemistry; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012542:Scattering, Radiation; D013056:Spectrophotometry, Ultraviolet
D008051:Lipid Bilayers; D008081:Liposomes; D010715:Phosphatidylglycerols; D010743:Phospholipids; D011838:Radiation-Sensitizing Agents; C002773:dimyristoylphosphatidylglycerol; D000638:Amiodarone; D004134:Dimyristoylphosphatidylcholine