Perturbing effects of carvedilol on a model membrane system: Role of lipophilicity and chemical structure

被引:33
作者
Butler, S
Wang, RW
Wunder, SL
Cheng, HY
Randall, CS
机构
[1] SanofiAventis Grp, Sanofi Synthelabo Res, Malvern, PA 19355 USA
[2] Temple Univ, Dept Chem 016 00, Philadelphia, PA 19122 USA
[3] GlaxoSmithKline, Phys & Analyt Methods, Collegeville, PA 19426 USA
关键词
carvedilol; beta-blocker; antioxidant; liposome; calorimetry; fluorescence;
D O I
10.1016/j.bpc.2005.09.004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Carvedilol, a beta-adrenergic blocker used to treat cardiovascular diseases, protects cell membranes from lipid peroxidative damage. Previous studies suggested the drug resides in a non-polar environment and partitions into cell membranes, perturbing their fluidity. Here differential scanning calorimetry (DSC) and fluorescence spectroscopy were applied to further investigate interactions of carvedilol with a liposome model. Results indicate the association is relatively unaffected by pH or temperature, but could be sensitive to liposome composition. The drug's carbazole group plays the dominant role in bilayer perturbation. Compared with other beta-blockers examined, carvedilol produced the strongest liposome DSC perturbation. Locations of carbazole and carvedilol in the liposome were determined using depth-dependent fluorescent probes. Both compounds are situated in the middle of the bilayer, consistent with strong hydrophobic interactions. This combination of high lipophilicity and specific chemical structure appear required for carvedilol's novel antioxidant activity, and may enhance cardioprotection. (C) 2005 Elsevier B.V. All rights reserved.
引用
收藏
页码:307 / 315
页数:9
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