OXIDIZED PHOSPHOLIPIDS AS POTENTIAL NOVEL DRUG TARGETS
Juha-Pekka Mattila 1, Karen Sabatini 1 and Paavo K. Kinnunen 1*
1 University of Helsinki Institute of Biomedicine
* To whom correspondence should be addressed. E-mail: paavo.kinnunen{at}helsinki.fi.
Submitted on January 4, 2007
Revised on February 23, 2007
Accepted on 13 June 2007
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Abstract |
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The interactions of three therapeutic agents, viz. the antipsychotics haloperidol and chlorpromazine, and the antineoplastic anthracycline doxorubicin, 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 phosphatidylcholines bearing either an aldehyde or carboxylic function at the end of the sn-2 nonanoyl chain, with the highest affinity measured between chlorpromazine 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. The present 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.
Key Words:
drug-lipid interactions, fluorescence quenching, oxidized phospholipids, reactive oxygen species
