Anthracycline binding to synthetic and natural membranes. A study using resonance energy transfer.
The binding of adriamycin and its two analogues 4'-epidoxorubicin and 4'-deoxydoxorubicin to synthetic and mitochondrial membranes was investigated by using resonance energy transfer between these drugs and two fluorescent probes, diphenylhexatriene (DPH) and tryptophan. The fluorescence of the lipid probe DPH in both types of membranes and tryptophan in mitochondria was quenched by the anthracyclines in a dose-dependent manner. In sonicated, fluid-phase dimyristoyl-L-alpha-phosphatidylcholine (DMPC) vesicles, the half-quenching concentration (K50) of adriamycin was 17 +/- 1 microM, whereas in bilayers containing a 1:1 molar ratio of DMPC to cardiolipin (CL), the value was 8 +/- 1 microM. In liver and heart mitochondria, the K50 values were 8 +/- 2 and 11 +/- 3 microM, respectively. Similar results were obtained for the other two drugs. Replacing a nonionic with an ionic medium or decreasing the pH from pH 7.7 to pH 6.9 increased the K50 value of adriamycin for DPH in DMPC/CL (1:1 molar) liposomes and in mitochondria. Higher concentrations of anthracycline were needed to quench the fluorescence of tryptophan. The results suggest that these drugs interact with both phospholipids and proteins and that the cardiotoxicity of adriamycin is unlikely to be related to the amount of drug bound to heart mitochondria.
Griffin
E A
EA
Vanderkooi
J M
JM
Maniara
G
G
Erecińska
M
M
D000818:Animals; D002308:Cardiolipins; D004134:Dimyristoylphosphatidylcholine; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D015251:Epirubicin; D007425:Intracellular Membranes / Q000378:metabolism*; D007700:Kinetics; D008081:Liposomes; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D051381:Rats; D013050:Spectrometry, Fluorescence / Q000379:methods; D013237:Stereoisomerism; D013816:Thermodynamics
D002308:Cardiolipins; D008081:Liposomes; D015251:Epirubicin; D004317:Doxorubicin; C030851:esorubicin; D004134:Dimyristoylphosphatidylcholine