Selective membrane toxicity of aminoglycoside antibiotics in membrane vesicles isolated from proximal renal tubules of the rat.
A considerable body of evidence suggests that the nephrotoxic potential of aminoglycoside antibiotics may be associated with the degree of membrane binding and subsequent membrane damage in the renal tubules. In this study, we isolated functional basolateral and luminal membrane vesicles from rat renal cortex, incubated each membrane type in the presence of 1 mM concentrations of either neomycin, netilmicin, gentamicin, hydroxygentamicin, or amikacin, and monitored the activities of the marker enzymes alkaline phosphatase (ALP) and lambda-glutamyltransferase (GGT) (luminal) or ouabain-sensitive Na+,K+-ATPase (basolateral) to determine if there were any selective drug-related alterations of enzyme activities. While none of the five aminoglycosides had any substantive effect upon enzyme activities of luminal vesicles, all five drugs inhibited the basolateral marker enzyme. Neomycin produced the greatest inhibition, hydroxygentamicin and amikacin the least, and gentamicin and netilmicin were intermediate in the inhibition of the enzyme. These results are in accordance with the known relative nephrotoxicity of these same drugs and indicate the usefulness of isolated renal membrane vesicles for in vitro toxicological studies of novel aminoglycosides.
Amacher
D E
DE
Drug Safety Evaluation Department, Pfizer Central Research, Groton, CT 06340.
Schomaker
S J
SJ
Meyers
L L
LL
D000469:Alkaline Phosphatase / Q000032:analysis; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis; D002462:Cell Membrane / Q000187:drug effects; D046508:Culture Techniques; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis / Q000037:antagonists & inhibitors; D005723:gamma-Glutamyltransferase / Q000032:analysis
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D015415:Biomarkers; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D000254:Sodium-Potassium-Exchanging ATPase