The interactions of amphotericin B with various sterols in relation to itspossible use in anticancer therapy

Amphotericin B (AmB) is still the most common anti-fungal agent used to tre at systemic fungal infections. It is known that this antibiotic acts by for ming pores with the ergosterol contained in the membranes of fungi, but it also interacts with the cholesterol contained in the membranes of eukaryoti c cells, hence its toxicity. AmB may also interact with the most common oxi dation products of cholesterol found in vivo, together with interacting wit h biosynthetic precursors of cholesterol, namely, lanosterol and 7-dehydroc holesterol (7-DHC). The purpose of the present work was to study the intera ctions in solution between AmB and these various sterols, the techniques us ed being UV-Vis spectroscopy and differential scanning calorimetry. The res ults are globally interpreted in terms of the structural differences betwee n the sterols. We show that AmB selectively interacts with 7-DHC which, acc ording to a recent hypothesis proposed in the literature, has been identifi ed in connexion with a therapeutic strategy against hepatocellular carcinom as. We find that the affinity of AmB towards 7-DHC is even greater than the affinity of the antibiotic towards ergosterol. We also find that AmB selec tively interacts with the principal oxidation product of cholesterol, 7-ket ocholesterol, a situation that has to be taken into account when AmB is adm inistered. (C) 2001 Elsevier Science B.V. All rights reserved.