JOINT INTERACTIONS OF ETHANOL AND DRUGS WITH BIOMEMBRANE

乙醇和药物与生物膜的联合相互作用

基本信息

批准号：
3445271
负责人：
BARRY B MUHOBERAC
金额：
$ 5.48万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-09-01 至 1988-08-31
项目状态：
已结题

项目摘要

This study will focus on the acute effects of ethanol in combination with other commonly used drugs on biomembrane structure and both enzyme and receptor function. Among the drugs to be studied are pentobarbital, chlorpromazine, and diazepam. Such drugs, in the presence of ethanol, are associated with enhanced psychomotor impairment and respiratory depression. Separately these drugs and ethanol alter membrane fluidity. Furthermore, pentobarbital and ethanol exhibit cross-tolerance in both inhibition of the righting reflex of the rat and perturbation of fluidity in mice synaptosomal membranes. Indeed, there is much evidence that the physiological effects of ethanol alone and of many other drugs are connected with the fluidization, penetration, and/or alteration of transition temperatures of cell membranes. Such parameters will be quantitated in synaptosomal and liver plasma membranes by ESR spectroscopy under varying perturbant conditions. Once significant structural alterations are verified, changes in activities of membrane-bound enzymes such as the Na+/K+ dependent ATPase and acetylcholinesterase, as well as changes in receptor binding of 3-quinuclidinyl benzilate and 5-hydroxytryptamine will be monitored. Emphasis will be placed on whether the ethanol-drug combination is synergistic, additive, or antagonistic in altering structure, function or both. Significant correlations between changes in biomembrane structure and enzymatic activity or receptor binding will suggest a more general involvement of membrane structure in such changes versus enzyme or receptor specific alterations. The determination of the effects of perturbants on the structural parameters of protein-free phospholipid vesicles formed from extracts of plasma membranes and from commercial sources will further distinguish between membrane-perturbant in contrast with protein-perturbant interactions. This study should enhance our understanding of the heretofore sparsely investigated response of biomembranes to simultaneous exposure to ethanol and other drugs. It will explore the hypothesis that part of the potentiating effects of simultaneously administered drugs on the higher functions of complex organisms orginates with synergistic changes in membrane structure. Furthermore, it may find an enzyme or receptor which might be particularly susceptible to the combination of ethanol and a drug in low (possibly clinically relevant) concentrations.

这项研究将重点关注乙醇与其他常用药物影响生物膜结构以及酶和受体功能。待研究的药物包括戊巴比妥、氯丙嗪和地西泮。此类药物在乙醇存在下与增强的精神运动障碍和呼吸系统障碍有关沮丧。这些药物和乙醇分别改变膜的流动性。此外，戊巴比妥和乙醇在两者中都表现出交叉耐受性。抑制大鼠翻正反射和扰动流动性在小鼠突触体膜中。事实上，有很多证据表明单独乙醇和许多其他药物的生理作用是与流化、渗透和/或改变有关细胞膜的转变温度。这样的参数将是通过 ESR 光谱法对突触体和肝脏质膜进行定量在不同的扰动条件下。曾经具有重大结构意义改变得到验证，膜结合酶活性的变化例如 Na+/K+ 依赖性 ATP 酶和乙酰胆碱酯酶，以及 3-奎宁环苯苯甲酸受体结合的变化和将监测 5-羟色胺。重点将放在是否乙醇-药物组合在以下方面具有协同作用、相加作用或拮抗作用改变结构、功能或两者兼而有之。之间的显着相关性生物膜结构和酶活性或受体结合的变化将建议膜结构更普遍地参与此类相对于酶或受体特异性改变的变化。决心干扰物对无蛋白质结构参数的影响由质膜提取物和从质膜提取物形成的磷脂囊泡商业来源将进一步区分膜扰动与蛋白质扰动相互作用形成对比。这项研究应该可以增强我们对迄今为止稀疏的知识的理解研究生物膜对同时暴露于乙醇的反应和其他药物。它将探讨以下假设：同时给药的药物对较高者的增强作用复杂生物体的功能源于协同变化膜结构。此外，它可能会发现一种酶或受体可能对乙醇和药物的组合特别敏感低浓度（可能与临床相关）。