Comparison of the effects of clozapine, chlorpromazine, and haloperidol on membrane lateral heterogeneity.
The interactions of three neuroleptic drugs, clozapine (CLZ), chlorpromazine (CPZ), and haloperidol (HPD) with phospholipids were compared using DSC and Langmuir balance. Main emphasis was on the drug-induced effects on the lateral organization of lipid mixtures of the saturated zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and the unsaturated acidic phosphatidylserine, brainPS. In multilamellar vesicles (MLV) phase separation was observed by DSC at X(PS)> or =0.05. All three drugs bound to these MLVs, abolishing the pretransition at X(drug)> or =0.03. The main transition temperature (T(m)) decreased almost linearly with increasing contents of the drugs, CLZ having the smallest effect. In distinction from the other two drugs, CLZ abolished the phase separation evident in the endotherms for DPPC/brainPS (X(PS)=0.05) MLVs. Compression isotherms of DPPC/brainPS/drug (X(PS)=X(drug)=0.05) monolayers revealed the neuroleptics to increase the average area/molecule, CLZ being the most effective. Penetration into brainPS monolayers showed strong interactions between the three drugs and this acidic phospholipid (in decreasing order CPZ>HPD>CLZ). Hydrophobic interactions demonstrated using neutral eggPC monolayers decreased in a different order, CLZ>CPZ>HPD. Fluorescence microscopy revealed domain morphology of DPPC/brainPS monolayers to be modulated by these drugs, increasing the gel-fluid domain boundary length in the phase coexistence region. To conclude, our data support the view that membrane-partitioning drugs could exert part of their effects by changing the lateral organization and thus also the functions of biomembranes.
Jutila
A
A
Helsinki Biophysics and Biomembrane Group, Institute of Biomedicine/Biochemistry, P.O. Box 63 (Haartmaninkatu 8), FIN-0014 University of Helsinki, Helsinki, Finland.
Söderlund
T
T
Pakkanen
A L
AL
Huttunen
M
M
Kinnunen
P K
PK
D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002746:Chlorpromazine / Q000378:metabolism / Q000494:pharmacology*; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology*; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D008567:Membranes, Artificial; D008856:Microscopy, Fluorescence / Q000379:methods
D014150:Antipsychotic Agents; D008081:Liposomes; D008563:Membrane Lipids; D008567:Membranes, Artificial; D003024:Clozapine; D006220:Haloperidol; D002746:Chlorpromazine