Oxidized phospholipids as potential novel drug targets.
The interactions of three therapeutic agents, viz. the antipsychotics HPD and CPZ, and the antineoplastic anthracycline DOX, with oxidatively modified phospholipids were studied by monitoring the quenching of fluorescence of an incorporated pyrene-labeled lipid derivative. All three drugs bound avidly to the two oxidized PCs bearing either an aldehyde or carboxylic function at the end of the sn-2 nonanoyl chain, with the highest affinity measured between CPZ and the latter oxidized lipid. Subsequent dissociation of the above drugs from the oxidized lipids by DNA, acidic phospholipids, and NaCl revealed the binding of these drugs with the aldehyde lipid to be driven by hydrophobicity similarly to their binding to lysophosphatidylcholine, whereas a significant contribution of electrostatics was evident for the lipid with the carboxylic moiety. These results connect to previous experimental data, demonstrating the induction by these drugs of oxidative stress and binding to membrane phospholipids. These issues are elaborated with reference to their clinical use and side effects.
Mattila
Juha-Pekka
JP
Helsinki Biophysics and Biomembrane Group, Institute of Biomedicine/Medical Biochemistry, FIN-00014, University of Helsinki, Helsinki, Finland.
Sabatini
Karen
K
Kinnunen
Paavo K J
PK
D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002746:Chlorpromazine / Q000378:metabolism / Q000494:pharmacology; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D016503:Drug Delivery Systems; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
D000903:Antibiotics, Antineoplastic; D014150:Antipsychotic Agents; D010713:Phosphatidylcholines; D004317:Doxorubicin; D006220:Haloperidol; D002746:Chlorpromazine