Evaluation of membrane fluidity effects and enzyme activities alterations in adriamycin neurotoxicity.
Adriamycin (ADR) increased the lipid fluidity of dog brain synaptosomal plasma membranes (SPM) labeled with 1,6-diphenyl-1,3,5-hexatriene (DPH), as indicated by the steady-state fluorescence anisotropy [(ro/r)-1]-1. Arrhenius-type plots of [(ro/r)-1]-1 indicated that the lipid phase separation of the membrane at 23.3 +/- 1.2 degrees was perturbed by ADR such that the temperature was reduced to 16.2 +/- 1.1 degrees. Arrhenius plots of (Na+ + K+)-stimulated ATPase activity exhibited a break point at 22.8 +/- 1.1 degrees in control SPM which was reduced to 15.8 +/- 1.0 degrees in ADR treated SPM, suggesting differences in the interaction of (Na+ + K+)-stimulated ATPase with lipids between ADR treated and untreated SPM. (Na+ + K+)-stimulated ATPase and Ca2+-stimulated ATPase activities were increased at a concentration range 10(-18)-10(-15) M of ADR; higher concentrations (up to 10(-7) M), however, led to a progressive inhibition of the enzyme activities. The allosteric properties of SPM-bound (Na+ + K+)-stimulated ATPase by fluoride (F-) (as reflected by changes in the Hill coefficient) were modulated by ADR whereas those of SPM-bound acetylcholinesterase remained unaffected. We propose that ADR achieves these effects through asymmetric perturbations of the membrane lipid structure and that changes in membrane fluidity may be an early key event in ADR induced neurotoxicity.
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004285:Dogs; D004317:Doxorubicin / Q000633:toxicity*; D005454:Fluorescence Polarization; D007700:Kinetics; D008315:Malondialdehyde / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects*; D009498:Neurotoxins; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D013816:Thermodynamics
D009498:Neurotoxins; D008315:Malondialdehyde; D004317:Doxorubicin; D000110:Acetylcholinesterase; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium