Presence of anionic phospholipids rules the membrane localization of phenothiazine type multidrug resistance modulator.
Substances able to modulate multidrug resistance (MDR), including antipsychotic phenothiazine derivatives, are mainly cationic amphiphiles. The molecular mechanism of their action can involve interactions with transporter proteins as well as with membrane lipids. The interactions between anionic phospholipids and MDR modulators can be crucial for their action. In present work we study interactions of 2-trifluoromethyl-10-(4-[methanesulfonylamid]buthyl)-phenothiazine (FPhMS) with neutral (PC) and anionic lipids (PG and PS). Using microcalorimetry, steady-state and time-resolved fluorescence spectroscopy we show that FPhMS interacts with all lipids studied and drug location in membrane depends on lipid type. The electrostatic attraction between drug and lipid headgroups presumably keeps phenothiazine derivative molecules closer to surface of negatively charged membranes with respect to neutral ones. FPhMS effects on bilayer properties are not proportional to phosphatidylserine content in lipid mixtures. Behavior of equimolar PC:PS mixtures is similar to pure PS bilayers, while 2:1 or 1:2 (mole:mole) PC:PS mixtures resemble pure PC ones.
Wesołowska
Olga
O
Department of Biophysics, Wrocław Medical University, ul. Chałubinskiego 10, 50-368 Wrocław, Poland. olawes@biofiz.am.wroc.pl
Hendrich
Andrzej B
AB
Motohashi
Noboru
N
Kawase
Masami
M
Dobryszycki
Piotr
P
Ozyhar
Andrzej
A
Michalak
Krystyna
K
D000838:Anions / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002412:Cations / Q000737:chemistry; D002463:Cell Membrane Permeability; D018432:Drug Resistance, Multiple; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry*; D010640:Phenothiazines / Q000737:chemistry*; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013696:Temperature
D000838:Anions; D002412:Cations; D008051:Lipid Bilayers; D010640:Phenothiazines; D010718:Phosphatidylserines; D010743:Phospholipids