Molecular parameters involved in aminoglycoside nephrotoxicity

Abstract

Aminoglycoside antibiotics are hydrophilic molecules consisting of an animated cyclitol associated with amino sugar. They bind in vivo as well as in vitro to negatively charged membranes. Their use as chemotherapeutic agents is unfortunately accompanied by oto- and nephrotoxic reactions, and the purpose of this review is to examine the role of the molecular interactions between aminoglycosides and membranes in the development of nephrotoxicity. 31P Nuclear magnetic resonance (NMR) and fluorescence depolarization have been used to characterize the effect of aminoglycosides on phosphate heads and fatty acyl chains of phospholipids. 15N NMR has been used to obtain interesting information on regioselective interactions of amino groups of antibiotics with phospholipids. The binding of aminoglycosides with negatively charged membranes is associated with impairment of phospholipid catabolism, change in membrane permeability, and membrane aggregation. Biochemical analysis and 1H NMR spectroscopy have brought information on the molecular mechanism involved in the impairment of phospholipid catabolism. Nephrotoxic aminoglycosides could induce sequestration of phosphatidylinositol and therefore reduce the amount of negative charge available for optimal lysosomal phospholipase activity toward phosphatidylcholine included in liposomes that also contain cholesterol and sphingomyelin. Conformational analysis shows that aminoglycosides, which have a high potency to inhibit lysosomal phospholipase activity, adopt an orientation parallel to the lipid/water interface. This orientation of the aminoglycoside molecule at the interface is also critical to explain the marked increase of membrane permeability induced by less nephrotoxic aminoglycosides such as isepamicin and amikacin. This effect is indeed only observed with aminoglycosides oriented perpendicular to this interface, probably related to the creation of a local condition of disorder. The impairment of phospholipid catabolism, which is considered to be an early and significant step in the development of aminoglycoside toxicity, is therefore not related to the change in membrane permeability. However, the role of this latter phenomenon and of membrane aggregation for aminoglycoside nephrotoxicity could be further investigated.