Benzodiazepine-induced changes in biomembrane fluidity.
Benzodiazepine-induced changes in biomembrane fluidity.
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苯二氮卓引起的生物膜流动性变化。
DOI：
10.1042/bst020157s
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发表时间：
1992
影响因子：
3.9
通讯作者：
C. Restall
中科院分区：
文献类型：
--
作者：
H. Kurishingal;P. Brain;C. Restall
苯二氮卓类药物是一类精神活性药物，因其抗焦虑、肌肉松弛和抗惊厥特性而被广泛处方。它们的使用与一些副作用有关，这些副作用仍然知之甚少。其中重要的一点是，孕妇接触某些精神活性药物可能会对其后代的发育和随后的行为产生持久的影响。例如，安定(广泛用于治疗抑郁症)与新生儿的一系列并发症有关，包括低眼压、低体温、高胆红素血症、窒息和呼吸障碍--统称为“软性婴儿综合症”。苯二氮卓类受体与γ-氨基丁酸(GABA)受体C21紧密偶联并相互作用。事实上，苯二氮卓类药物没有内在作用，而是通过增强GABA增加氯离子通道通透性的能力来发挥作用。因此，苯二氮卓类药物的作用通常几乎完全根据它们对GABA复合体的作用来考虑。然而，重要的是要认识到，其他物质以其他方式产生一些活动。例如，早期接触乙醇引起的行为变化似乎更多地与这种非特异性药物对膜流动性C31的作用有关。因此，存在这样一种可能性，即其他支付活性药物(或其副作用)的至少部分持久影响可能是以类似的方式引起的。为了进一步研究这种可能性，我们研究了两种苯二氮卓类激动剂和一种拮抗剂对膜流动性的影响。将卵黄磷脂酰胆碱分散于20CmM Tris-C1pH 7.2溶液中，超声分散后制成单层脂质体，制得脂质双层膜。然后用1，B-二苯基-1，3，5-己三烯(DPH)标记所得的膜，得到1：500的探针-脂比。使用Perkin-Elmer LS5-B发光光谱仪进行荧光偏振测量，如在别处C41所述。数据用发射各向异性(R)来表示，其中r=(IW-IVH)/(IW+2IVH)。Iw和IVh分别是平行于激发光偏振面和垂直于激发光偏振面的发射强度。所有测量都在25℃下进行。添加不同量的氯氮卓酮(CDP)、安定和Ro15-1788的结果如图1所示。很明显，CDP和安定都能够在较低的生理相关浓度下使膜流态化。然而，安定的作用更为明显。通过比较，对拮抗剂RO15-1788的结果表明，该化合物对膜的干扰作用甚至比激动剂更有效。
The benzodiazepines are a group of psychoactive drugs which are extensively prescribed for their anxiolytic, muscle-relaxant and anticonvulsant properties. Their use has been associated with a number of side-effects which remain poorly understood. Significant amongst these is the possibility that exposure of pregnant women to certain psychoactive drugs may have lasting impacts on development and subsequent behaviour of their offspring. For example, diazepam (much used in the treatment of depression) has been associated with a number of complications in the newborn infant including hypotonia, hypothermia, hyperbilirubinaemia, asphyxia and breathing disorders-collectively known as the'floppy infant syndrome'Cll. Benzodiazepine receptors are closely coupled to and interact with gamma-amino butyric acid (GABA) receptors C21. Indeed, benzodiazepines do not have intrinsic actions but act by enhancing the ability of GABA to increase the permeability of the chloride ion channel. As a consequence, the actions of the benzodiazepines are usually considered almost exclusively in terms of their actions on the GABA complex. However, it is important to realise that other substances produce some of their actions in other ways. For example, the behavioural changes induced by early exposure to ethanol appear more related to the action of this non-specific drug on membrane fluidity C31. The possibility thus exists that at least some of the lasting influences of other paychoactive drugs (or their side-effects) may be induced in a similar manner. To investigate this possibility further, the effects on membrane fluidity of two benzodiazepine agonists, together with an antagonist have been studied. Lipid bilayer membranes were prepared by dispersing egg-yolk phosphatidylcholine in 20CmM Tris-C1 pH 7.2 followed by sonication to produce unilamellar liposomes. The resulting membranes were then labelled with 1, B-diphenyl 1, 3, 5-hexatriene (DPH) to give a probe-lipid ratio of 1: 500. Fluorescence polarization measurements were performed using a Perkin-Elmer LS5-B luminescence spectrometer as described elsewhere C41. The data are expressed in terms of the emission anisotropy,(r) where r=(Iw-Ivh)/(Iw+ 2Ivh). I w and Ivh being the emission intensities observed parallel and perpendicular respectively to the polarization plane of the exciting light. All measurements were performed at 25 C.The results of adding varying quantities of chlordiazepoxide (CDP), diazepam and Ro 15-1788 are shown in Figure 1. It is evident that both CDP and diazepam are capable of fluidizing the membrane at low, physiologically-relevant concentrations. However, the effect of diazepam is more pronounced. By way of comparison, the results obtained for the antagonist Ro 15-1788 show that this compound is even more effective at perturbing the membrane than the agonists.