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Review
. 1999 May;43(5):1003-12.
doi: 10.1128/AAC.43.5.1003.

Aminoglycosides: nephrotoxicity

M P Mingeot-Leclercq  1 , P M Tulkens
Affiliations
Free PMC article
Review

Aminoglycosides: nephrotoxicity

M P Mingeot-Leclercq et al. Antimicrob Agents Chemother. 1999 May.
Free PMC article
No abstract available

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Figures

FIG. 1
FIG. 1
Ultrastructural alterations induced in proximal tubular cells during aminoglycoside treatment. (A) Control. Changes detected early on and at low doses (B) consist mainly of the enlargement of lysosomes, which most likely occurs by fusion of preexisting structures and which is caused by the progressive deposition of polar lipids which adopt a concentric lamellar disposition (myelin-like structures, most commonly referred to as myeloid bodies); the other subcellular structures are usually well preserved. Later changes or changes observed with high doses (C) include the apparent rupture of lysosomes (with the release of myeloid bodies in the cytosol), extensive mitochondrial swelling and damage, dilatation of the endoplasmic reticulum cisternae, shedding of the apical brush-border villi, pericellular membrane discontinuities, and the occurrence of apoptotic nuclei. These alterations do not necessarily coexist in all cells. The figure is adapted from reference and is based on the typical descriptions given in references , , , , , , and .
FIG. 2
FIG. 2
Skeleton views of the mode of assembly of gentamicin C1a and isepamicin (in green) with phosphatidylinositol (hydrocarbon is in grey and oxygen and phosphorus atoms are in red to clearly indicate the polar domain). The two isolated drug molecules, with the same orientation, are shown on the right for ease of identification of their various parts (carbons are in grey, oxygens are in red, and nitrogens are in blue; see Fig. 1 of the companion minireview [83] for the chemical structures of isepamicin and gentamicin C1a). The molecular modeling approach suggests that the orientations and the positions of the two drugs inserted in the phosphatidylinositol monolayer are entirely different. First, the N-6′ amino groups are oriented in opposite directions (toward the lipophilic phase in the case of gentamicin and toward the water phase for isepamicin. Second, gentamicin lies above the plane of the inositol moieties and far away from the water phase (bottom), whereas isepamicin is readily accessible and is probably therefore more easily displaceable. Similar differences have been noted between kanamycin A and amikacin (133). Since both isepamicin and amikacin are characterized by a side chain at position N-1, these differences have been ascribed to the presence of this side chain (note that the orientation and position of gentamicin C1a are very akin to those of gentamicin B, the parent, unsubstituted compound of isepamicin, and kanamycins). Such changes in position and orientation are thought to explain the lower inhibitory potential of amikacin and isepamicin toward the activities of phospholipases (for discussions, see references , , and 131). As outlined in this minireview and elsewhere (130, 133), inhibition of phospholipases is probably an important, early event in aminoglycoside nephrotoxicity. The figure was adapted from reference , with permission.
FIG. 3
FIG. 3
Structural modifications made in kanamycin A (R = OH) or kanamycin B (R = NH2) (these aminoglycosides are the most frequently used for chemical modifications) to obtain a modulation of the potential of the drug to cause lysosomal phospholipidosis in comparison with the structure of the corresponding parent compound. The figure is from references , , , , , , and .
See this image and copyright information in PMC

References

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