Evidence of a complex between adriamycin derivatives and cardiolipin: possible role in cardiotoxicity.
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Cardiolipins↗
Biomedical subjects
E Goormaghtigh
Publications and source records attributed to E Goormaghtigh.
Evidence of a specific complex between adriamycin and negatively-charged phospholipids.
Membrane-model systems (monolayers, small unilamellar vesicles) were used to study the interaction between adriamycin (ADM) and phospholipids. Adsorption of 3H-labeled adriamycin on different phospholipid monolayers demonstrated the specificity of adriamycin for negatively-charged phospholipids (cardiolipin, phosphatidylserine, phosphatidic acid). The stoichiometry has been found to be approx. 2 mol (1.8) adriamycin per mol cardiolipin and approx. 1 mol (0.75) adriamycin per mol phosphatidylserine and phosphatidic acid. No adsorption was detected with neutral lipids. Surface-potential measurements confirm the formation of a complex stabilized by electrostatic interactions without penetration of the drug into the lipid lipophilic phase. Some adriamycin derivatives were used to discriminate between the ionized hydrophilic and hydrophobic contributions in the complex formation. The absorption spectrum of adriamycin in the presence of cardiolipin resembles the behavior of the ADM-DNA complex. Moreover, the association constants of the two complexes are very similar (cardiolipin-ADM, 1.6 . 10(6) . M-1; ADM-DNA, 2.4 . 10(6) . M-1). To explain the high affinity of cardiolipin for adriamycin, we proposed that two essential interactions are responsible for the complex stabilization: an electrostatic interaction between the protonated amino groups of the sugar residues and the ionized phosphate residues, and an interaction between adjacent anthraquinone chromophores. These data strongly suggest competitive behavior between a membrane site and the target. Consequently, it must be assumed that the lipidic components of the cell membrane structure may be an important determinant in the behavior of adriamycin. This observation should be kept in mind in the building of new derivatives.
Calorimetry↗
Study of the adriamycin-acidic phospholipid complex in model membranes [proceedings].
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Animals↗
Hydrogen-deuterium exchange in membrane proteins monitored by IR spectroscopy: a new tool to resolve protein structure and dynamics.
As more and more high-resolution structures of proteins become available, the new challenge is the understanding of these small conformational changes that are responsible for protein activity. Specialized difference Fourier transform infrared (FTIR) techniques allow the recording of side-chain modifications or minute secondary structure changes. Yet, large domain movements remain usually unnoticed. FTIR spectroscopy provides a unique opportunity to record (1)H/(2)H exchange kinetics at the level of the amide proton. This approach is extremely sensitive to tertiary structure changes and yields quantitative data on domain/domain interactions. An experimental setup designed for attenuated total reflection and a specific approach for the analysis of the results is described. The study of one membrane protein, the gastric H(+),K(+)-ATPase, demonstrates the usefulness of (1)H/(2)H exchange kinetics for the understanding of the molecular movement related to the catalytic activity.
Adenosine Triphosphatases↗