title: Circular dichroism study of interactions of Fungizone or AmBisome forms of amphotericin B with human low density lipoproteins.
abstract: Amphotericin B (AmB), a potent antifungal agent used to treat invasive fungal infections, is still employed more than 40 years after its introduction in the pharmacopea. When injected into the blood stream, this antibiotic is carried by low density lipoproteins (LDLs) to which it induces the formation of oxidation products responsible in part for some of the severe adverse effects of the drug. However, the oxidative damages induced to LDLs are not yet understood. We present here the effects of the Fungizone and AmBisome forms of AmB on LDLs as compared to those of CuSO(4), a well-known powerful oxidant of LDLs. We use circular dichroism (CD) spectroscopy, which is particularly useful because it allows the investigation of the structural integrity of the proteic moiety of LDL upon interaction with AmB. The CD spectra also yield information on the drug itself because in its oligomer form it presents a strong dichroic signal in a spectral region different from that of the protein. Our results show that neither form of AmB changes the secondary structure of the protein while the helical content of the LDL is increased either in the presence of CuSO(4) alone or in the presence of CuSO(4) and AmBisome or Fungizone. On the other hand, the CD spectra of the antibiotic indicate that Fungizone AmB suffers important oxidative damage in the presence of LDLs and CuSO(4) while this damage is not present with AmBisome AmB. These observations lead us to propose that the structural modifications of the proteic part of LDLs induced by the Cu(2+) ions are involved in the important oxidative damage suffered by Fungizone AmB, which in this form is much more susceptible to interaction with its environment than AmBisome.
authors.affiliation: Département de Chimie-Biologie, Université du Québec à Trois-Rivières, B.P. 500, Trois-Rivières, Québec G9A 5H7, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Barwicz
authors.forename: Marc
authors.initials: M
authors.lastname: Beauregard
authors.forename: Pierre
authors.initials: P
authors.lastname: Tancrède
mesh_terms: D000666:Amphotericin B / Q000737:chemistry* / Q000378:metabolism; D000935:Antifungal Agents / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D019327:Copper Sulfate / Q000737:chemistry; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D017433:Protein Structure, Secondary
chemical_list: D000935:Antifungal Agents; D008077:Lipoproteins, LDL; C068538:liposomal amphotericin B; D000666:Amphotericin B; D019327:Copper Sulfate