ROLE OF ANIONIC PHOSPHOLIPIDS IN THE INTERACTION OF DOXORUBICIN AND PLASMA-MEMBRANE VESICLES - DRUG-BINDING AND STRUCTURAL CONSEQUENCES IN BACTERIAL SYSTEMS
ROLE OF ANIONIC PHOSPHOLIPIDS IN THE INTERACTION OF DOXORUBICIN AND PLASMA-MEMBRANE VESICLES - DRUG-BINDING AND STRUCTURAL CONSEQUENCES IN BACTERIAL SYSTEMS
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DOI：
10.1021/bi00077a023
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发表时间：
1993-07-06
期刊：
影响因子：
2.9
通讯作者：
DEKRUIJFF, B
中科院分区：
文献类型：
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作者：
DEWOLF, FA;STAFFHORST, RWHM;DEKRUIJFF, B
蒽环类药物-膜相互作用在蒽环类药物的运输、细胞质分布以及可能的活性中发挥作用。先前对模型膜的研究表明，广泛应用的抗癌药物阿霉素与阴离子磷脂特异性相互作用 [de Wolf, F. A., et al. （1991）生物化学。生物物理学。 Acta 106, 67-80]。我们现在已经能够直接在质膜中研究这些相互作用及其对阴离子磷脂的选择性。由于最近出现了大肠杆菌突变体，其中阴离子磷脂含量仅占总磷脂含量的 10% 到 100%，因此我们使用这种细菌作为质膜的来源。我们比较了阳离子蒽环类阿霉素与（1）不同突变菌株的质膜，（2）这些膜的总脂质提取物，以及（3）合成磷脂混合物（其中相当一部分磷脂带负电荷）的相互作用。结果表明，阴离子磷脂是阿霉素结合的重要决定因素，不仅在模型膜中而且在质膜系统中也是如此。只有在阴离子脂质含量非常低的质膜中，与阴离子磷脂的结合才被其他因素掩盖。使用在[11,11-H-2(2)]油酸上生长的不饱和脂肪酸营养缺陷型，从H-2-NMR数据看来，阿霉素会诱导细菌质膜及其总脂质提取物中酰基链的紊乱。这表明结合不是纯粹的静电结合，而是涉及药物分子插入脂质基质中，可能是由于疏水相互作用。
Anthracycline-membrane interactions play a role in the transport, the cytoplasmic distribution, and possibly also the activity of anthracyclines. Previous work on model membranes has shown that the widely-applied anticancer drug doxorubicin interacts specifically with anionic phospholipids [de Wolf, F. A., et al. (1991) Biochim. Biophys. Acta 106, 67-80]. We have now been able to investigate these interactions, and their selectivity for anionic phospholipids, directly in plasma membranes. Because of the recent availability of Escherichia coli mutants in which the anionic phospholipid content ranges from only 10% to as much as 100% of the total phospholipid content, we used this bacterium as a source of plasma membranes. We compared the interactions of the cationic anthracycline doxorubicin with (1) plasma membranes of different mutant strains, (2) total lipid extracts of these membranes, and (3) synthetic phospholipid mixtures in which a comparable fraction of the phospholipids was negatively charged. The results show that anionic phospholipids are important determinants of doxorubicin binding, not only in model membranes but also in plasma membrane systems. Only in plasma membranes with a very low anionic lipid content was the binding to the anionic phospholipid masked by other factors. Using an unsaturated fatty acid auxotroph grown on [11,11-H-2(2)]oleic acid, it appeared from H-2-NMR data that doxorubicin induces a disordering of acyl chains in bacterial plasma membranes and their total lipid extracts. This indicates that the binding is not purely electrostatic but involves the insertion of drug molecules into the lipid matrix, probably due to hydrophobic interactions.