Growth characteristics of cultured human proximal tubule cells exposed to aminoglycoside antibiotics.
It is well known that the nephrotoxic lesions that occur during aminoglycoside-induced nephrotoxicity are both dose- and time-dependent. It was the purpose of this study to determine if a cell culture model based on the human proximal tubule would exhibit similar dose- and time-dependent relationships when exposed to aminoglycosides of various nephrotoxic potential. For this determination, the human proximal tubule (HPT) cells were exposed to increasing concentrations of streptomycin, kanamycin, gentamicin, and neomycin and monitored for cell growth and toxicity over an 18-day period of exposure. Both actively-dividing and resting cells were assessed with regard to aminoglycoside exposure. At high levels of aminoglycoside exposure, linear regression analysis disclosed that the rank order of toxicity of the aminoglycosides to be: neomycin greater than kanamycin greater than gentamicin greater than streptomycin. Both actively-dividing and resting cultures of HPT cells displayed both dose- and time-dependency with regard to toxicity and the ability of the cells to regenerate in the continued presence of aminoglycoside exposure. This pattern of dose- and time-dependency was unique for each aminoglycoside and varied depending on the replicative state of the cells. With the exception of neomycin, clear evidence was obtained that toxicity and cell regeneration were occurring simultaneously throughout the time course of aminoglycoside exposure; the equilibrium between the two processes determining overall cell toxicity or regeneration. In addition, the HPT cells exposed to gentamicin displayed a unique pattern of toxicity and cell regeneration when compared to the other aminoglycosides tested, with gentamicin having an increased ability to stimulate cell proliferation. While the results obtained are in excellent agreement with that known from the clinical experience with the aminoglycosides, the dose- and time-dependency of the responses will require careful attention to growth state during employment in experimental protocols.
Department of Pathology, Medical University of South Carolina, Charleston 29425.
M A
MA
Sens
D J
DJ
Hazen-Martin
J G
JG
Blackburn
G R
GR
Hennigar
D A
DA
Sens
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008954:Models, Biological; D013997:Time Factors
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents