1: J Toxicol Environ Health 1995 Mar;44(3):263-300
Molecular parameters involved in aminoglycoside nephrotoxicity.
Mingeot-Leclercq MP, Brasseur R, Schanck A
Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique
de Louvain, Brussels, Belgium.
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 equestration 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.
Publication Types:
Review
Review, academic
PMID: 7897692, UI: 95205446