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