Steinkopf Signe, Schelderup Anja Katrin, Gjerde Hanne Linn, Pfeiffer Jeanette, Thoresen Synnøve, Gjerde Anja Underhaug, Holmsen Holm
Department of Biomedical Laboratory Science, Bergen University College, Bergen, Norway.
Biophys Chem. 2008 Apr;134(1-2):39-46. doi: 10.1016/j.bpc.2008.01.003. Epub 2008 Jan 17.
The typical antipsychotics chlorpromazine (CPZ) and trifluoperazine (TFP) increase the mean molecular area (mma) of acidic, but not neutral, glycerophospholipids in monolayers at pH 7.36 measured by the Langmuir technique. The atypical antipsychotic olanzapine (OLP(1)) is structurally similar to TFP. We have therefore studied the effects of OLP on glycerophospholipid monolayers and in comparison with CPZ. Olanzapine (10 microM, in subphase, pH 7.36) influenced the isotherms (surface pressure versus mma) in monolayers of the neutral dipalmitoyl phosphatidylcholine (DPPC) and the acidic dipalmitoyl phosphatidylserine (DPPS) or 1-palmitoyl-2-oleoylphosphatidylserine (POPS) in the increasing order of mma: DPPS<DPPC<POPS at both lower and higher temperature. Thus, presence of an unsaturated acyl in PS increased the drug-induced effect on mma. The mma in the absence of drugs was lower at lower temperatures than at higher temperatures. OLP affected mma to a greater extent than CPZ, and caused the greatest interaction at surface pressure of 30 mN/m at higher temperatures. In contrast, CPZ gave the largest effect in the monolayers at surface pressure 30 mN/m at lower temperatures. CPZ did not alter the isotherms of DPPC, at lower or higher temperature, and only affected the packing of the DPPS and POPS monolayers. In contrast, OLP altered the isotherms of DPPC. It is suggested that the drugs affect the monolayer packing by intercalating between the glycerophospholipid molecules. Since CPZ has major side effects, while OLP has few, this may indicate that there is poor correlation between side effects and effects of the drugs on phospholipid monolayers.
典型抗精神病药物氯丙嗪（CPZ）和三氟拉嗪（TFP）可增加单层酸性甘油磷脂（而非中性甘油磷脂）的平均分子面积（mma），该实验在pH 7.36条件下采用朗缪尔技术进行测量。非典型抗精神病药物奥氮平（OLP(1)）在结构上与TFP相似。因此，我们研究了OLP对甘油磷脂单层的影响，并与CPZ进行比较。奥氮平（亚相中浓度为10 microM，pH 7.36）影响了中性二棕榈酰磷脂酰胆碱（DPPC）以及酸性二棕榈酰磷脂酰丝氨酸（DPPS）或1-棕榈酰-2-油酰磷脂酰丝氨酸（POPS）单层的等温线（表面压力与mma的关系），在较低和较高温度下，mma的增加顺序均为：DPPS<DPPC<POPS。因此，PS中不饱和酰基的存在增强了药物对mma的诱导作用。在无药物存在时，较低温度下的mma低于较高温度下的mma。OLP对mma的影响程度大于CPZ，且在较高温度下表面压力为30 mN/m时产生的相互作用最大。相比之下，CPZ在较低温度下表面压力为30 mN/m时在单层中产生的影响最大。CPZ在较低或较高温度下均未改变DPPC的等温线，仅影响了DPPS和POPS单层的堆积。相比之下，OLP改变了DPPC的等温线。研究表明，这些药物通过插入甘油磷脂分子之间来影响单层堆积。由于CPZ有主要副作用，而OLP副作用较少，这可能表明副作用与药物对磷脂单层的作用之间相关性较差。
