Characterization of aminoglycoside-lipid interactions and development of a refined model for ototoxicity testing.
Characterization of aminoglycoside-lipid interactions and development of a refined model for ototoxicity testing.
复制标题
氨基糖苷-脂质相互作用的表征和耳毒性测试的精细模型的开发。
DOI：
10.1016/0006-2952(84)90087-x
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发表时间：
1984
影响因子：
5.8
通讯作者：
Schacht,J
中科院分区：
文献类型：
--
作者：
Wang,BM;Weiner,ND;Takada,A;Schacht,J
在三种模型系统中测量了氨基糖苷类与各种磷脂的相互作用，并与药物的耳毒性进行了比较：（a）[14 C]新霉素结合的竞争;（B）45 Ca 2+结合的竞争;和（c）对单分子脂质膜表面压力的影响。从磷脂酰丝氨酸、磷脂酰肌醇和磷脂酰肌醇二磷酸中置换新霉素的效果为奈替米星>新霉素>庆大霉素;从磷脂酰肌醇、磷脂酰肌醇磷酸和磷脂酰肌醇二磷酸中置换钙的效果为奈替米星>庆大霉素>新霉素>卡那霉素>大观霉素。这两项指标均与耳蜗灌注中等摩尔药物浓度下定量的药物的耳毒性相关性不好：新霉素>庆大霉素≥妥布霉素>奈替米星≥阿米卡星。当单分子膜的磷脂酰胆碱与磷脂酰丝氨酸，心磷脂，磷脂酰肌醇，或磷脂酰肌醇磷酸或二磷酸与新霉素的挑战，磷脂酰肌醇二磷酸膜表现出独特的剂量依赖性增加的表面压力，而其他人表现出减少或没有显着的效果。氨基糖苷类增加磷脂酰胆碱：磷脂酰肌醇二磷酸（1：1摩尔比）的膜的表面压力的能力在3 mM氯化钙的存在下，以及与它们的毒性相关。非耳毒性阳离子增加膜压力或使其不受影响。结果证实了氨基糖苷类和磷脂酰肌醇二磷酸之间的独特的相互作用作为一个可能的基础的机制的毒性和药物筛选系统的发展。
Aminoglycoside interactions with various phospholipids were measured in three model systems and compared with the ototoxicities of the drugs: (a) competition for [14C]neomycin binding; (b) competition for45Ca2+binding; and (c) effect on surface pressure of monomolecular lipid films. The efficacies of the antibiotics in displacing neomycin from phosphatidylserine, phosphatidylinositol or phosphatidylinositol bisphosphate were netilmicin > neomycin ⩾ gentamicin; the efficacies in displacing calcium from phosphatidylinositol, phosphatidylinositol phosphate or phosphatidylinositol bisphosphate were netilmicin > gentamicin > neomycin > kanamycin > spectinomycin. Neither measure correlated well with the ototoxicities of the drugs which were quantitated at equimolar drug concentrations in cochlear perfusions: neomycin > gentamicin ≥ tobramycin > netilmicin ≥ amikacin. When monomolecular films of phosphatidylcholine with phosphatidylserine, cardiolipin, phosphatidylinositol, or phosphatidylinositol phosphate or bisphosphate were challenged with neomycin, the phosphatidylinositol bisphosphate film showed a unique dose-dependent increase in surface pressure while the others showed a decrease or no significant effect. The abilities of aminoglycosides to increase the surface pressure of a film of phosphatidycholine : phosphatidylinositol bisphosphate (1:1 molar ratio) in the presence of 3 mM CaCl2correlated well with their toxicities. Non-ototoxic cations increased the film pressure or left it unaffected. The results confirm the unique interactions between aminoglycosides and phosphatidylinositol bisphosphate as a possible basis of a mechanism of toxicity and development of a drug-screening system.