An investigation of possible mechanisms of toxicity of the aminoglycoside antibiotics

Abstract

A study was made of possible mechanisms of uptake and toxicity
of the aminoglycoside antibiotics, in particular gentamicin.

The uptake of gentamicin was characterised in rat kidney
cortical slices and in isolated rat renal proximal tubules. In
each case, the uptake of gentamicin was found to be both time and
concentration dependent, showing saturable characteristics. The
use of metabolic inhibitors suggested that the process was energy
dependent.

Isolated rat renal tubules were used as a model system since
they offer advantages over cortical slices of better oxygenation
and substrate availability to the tubular cells. The preparation
and characterisation of the tubules is described.

The release of the lysosomal enzymes acid phosphatase and
N-acetyl-8-glucosaminidase from these tubules on incubating in the
presence of gentamicin was also studied. The release was a function
of a complex interaction between the gentamicin concentration and
the time of incubation. The findings were interpreted as a
disturbance by gentamicin of receptor-recycling by a differential
effect on the two lysosomal enzyme transport pathways.

Gentamicin inhibited gluconeogenesis but did not effect protein
synthesis.

the interaction of aminoglycosides with plasma membrane
Na + -K+ ATPase as a common mechanism of drug-induced nephrotoxicity
and ototoxicity is discussed.

A comparison was made of the urinary excretion of the enzymes
lactate dehydrogenase, N-acetyl-8-glucosaminidase and alanine aminopeptidase
with other indices of renal function in rats injected
with gentamicin (40 mg/kg/day). The results confirmed that the
early appearance of enzymes in urine is a sensitive indicator of
kidney damage.

It is suggested that isolated rat renal tubules may be used
as a relevant model for assessing toxic effects of new aminoglycosides

Date of Award	1981
Original language	English