Amphotericin B protects cis-parinaric acid against peroxyl radical-induced oxidation: amphotericin B as an antioxidant.
The antifungal effects of amphotericin B are believed to be due to two possibly interrelated mechanisms: an increase in permeation by binding to sterols in cellular membranes and a prooxidant effect causing oxidative damage in target cells. However, the seven conjugated double bonds in amphotericin B raise the possibility that it could be highly susceptible to autoxidation, causing an antioxidant effect. In the present study, we investigated the prooxidant and antioxidant properties of amphotericin B in a model system in which oxidation of a reporter molecule, cis-parinaric acid, was induced by azo initiators of peroxyl radicals. Since interactions of amphotericin B with sterols are essential for its pharmacological and toxic actions, we also studied the effects of cholesterol on the prooxidant and antioxidant properties of amphotericin B. Amphotericin B caused a noncollisional quenching of a characteristic fluorescence of cholesteryl cis-parinarate integrated in liposomes, suggesting the formation of amphotericin B-cholesteryl cis-parinarate complex. This effect of amphotericin B was ablated by increasing concentrations of cholesterol. We found that amphotericin B inhibited oxidation of cis-parinaric acid complexed with human serum albumin [using a water-soluble azo initiator, 2,2'-azobis(2aminopropane)dihydrochloride] and in liposomes [using a lipid-soluble azo initiator, 2,2'-azobis(2,4-dimethylvaleronitrile)]. The inhibitory effect of amphotericin B on 2,2'-azobis(2,4-dimethylvaleronitrile)-induced peroxidation of cis-parinaric acid in liposomes was also diminished by cholesterol. The antioxidant effect of amphotericin B in this model system suggests that amphotericin B does not exert its pharmacological and toxicological responses through a prooxidant effect to cause damage in target cells.
Osaka
K
K
Department of Environmental and Occupational Health, University of Pittsburgh, Pennsylvania 15238, USA.
Ritov
V B
VB
Bernardo
J F
JF
Branch
R A
RA
Kagan
V E
VE
D000666:Amphotericin B / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry; D008081:Liposomes; D010084:Oxidation-Reduction; D010545:Peroxides / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D005231:Fatty Acids, Unsaturated; D005609:Free Radicals; D008081:Liposomes; D010545:Peroxides; D000666:Amphotericin B; D002784:Cholesterol; C013641:parinaric acid