Partitioning and membrane disordering effects of dopamine antagonists: influence of lipid peroxidation, temperature, and drug concentration.
The effect of four dopamine antagonists (spiperone, haloperidol, pimozide, and domperidone) on the lipid order of caudate nucleus microsomal membranes and on liposomes from membrane lipid extracts was evaluated and related to the partition coefficients (Kp) of the drugs. Lipid membrane order was determined by fluorescence polarization using 1,6-diphenyl-1,3,5-hexatriene (DPH) as a probe of the membrane core and 1-[4-(trimethylammonium)phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH) as a probe of the membrane surface. Dopamine antagonists decrease the fluorescence polarization of both probes, indicating that they disorder the membrane lipids at different depths. Pimozide and domperidone, the drugs with higher Kp values, are more effective at decreasing the polarization of DPH, a probe of the membrane core, than that of TMA-DPH. In contrast, spiperone and haloperidol, which have lower values for Kp, induce more significant decreases in TMA-DPH depolarization, a probe of the membrane surface. These findings indicate that higher partition coefficients of the drugs are directly correlated with an increase of fluidity in the hydrophobic core of brain membranes. Ascorbate/Fe(2+)-induced membrane lipid peroxidation increases membrane order. Membrane lipid peroxidation decreases the partition coefficients of the dopamine antagonists tested. Increasing temperature (4-37 degrees C) decreases membrane order, but temperature effect is less evident after lipid peroxidation. The disordering effect of dopamine antagonists increases with increasing drug concentrations (1-15 microM), a maximum being observed at 10 microM. However, this effect is also less evident after membrane lipid peroxidation. We can conclude that dopamine antagonists and membrane lipid peroxidation affect membrane lipid order and that the action of these drugs is dependent on initial bilayer fluidity. Membrane lipid peroxidation increases membrane order while dopamine antagonists show a disordering effect of membrane phospholipids. This disordering effect can indirectly influence the activity of membrane proteins and it is one of the mechanisms through which membrane function can be altered by these drugs.
Palmeira
C M
CM
Department of Zoology, University of Coimbra, Portugal.
Oliveira
C R
CR
D000818:Animals; D002421:Caudate Nucleus / Q000737:chemistry* / Q000187:drug effects; D004161:Diphenylhexatriene / Q000031:analogs & derivatives / Q000494:pharmacology; D004294:Domperidone / Q000494:pharmacology; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D006358:Hot Temperature; D007425:Intracellular Membranes / Q000737:chemistry* / Q000187:drug effects; D015227:Lipid Peroxidation; D008081:Liposomes / Q000737:chemistry*; D008861:Microsomes / Q000737:chemistry* / Q000187:drug effects; D010868:Pimozide / Q000494:pharmacology; D012756:Sheep; D012995:Solubility; D013134:Spiperone / Q000494:pharmacology
D018492:Dopamine Antagonists; D008081:Liposomes; D004161:Diphenylhexatriene; D010868:Pimozide; D013134:Spiperone; D004294:Domperidone; C033628:1-(4-(trimethylamino)phenyl)-6-phenylhexa-1,3,5-triene; D006220:Haloperidol