Cephaloridine-induced biochemical changes and cytotoxicity in suspensions of rabbit isolated proximal tubules

Rush, Glenn F.; Ponsler, G. Douglas

doi:10.1016/0041-008x(91)90178-h

Cited by 24 publications

(15 citation statements)

References 22 publications

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“…In suspensions of intact proximal tubule segments, Cld has been shown to cause lipid peroxidation and decreases in ATP prior to 33). the onset of cell'death (leakage of lactate dehydrogenase [LDH]), suggesting a causal relationship between these biochemical changes and cell death (1 0, 20,21). These data are consistent with a recent report by Tune et al (32) suggesting that both peroxidative damage and mitochondrial injury may be involved in the nephrotoxicity of Cld.…”

Section: Introduc~ionsupporting

confidence: 82%

“…The reasons for this "overshoot" are not entirely clear but may be due to the loss of negative feedback control of GSH on y-glutamyl-cysteine synthetase (19). In these studies, as reported previously, the incubation media did not contain any of the amino acid precursors to GSH synthesis (22). In fact, these tubules contained only 7.20 +-1.35 nmol GSH/mg protein after 3 hr of incubation and were somewhat GSH depleted compared to in viw".…”

Section: Fig 8-continuedsupporting

confidence: 54%

“…In other words, cellular GSH was decreased to the greatest degree when the plasma Cld concentrations were highest and then recovered as the plasma Cld concentrations decreased. In iso--latea''@bbit tubules in vitro, 1.0 mM Cld caused marked GSH depretion, whereas 0.1 mM Cld causes only a modest GSH depletion (22). Therefore, the effects of Cld on renal GSH in vivo appear to be similar to those observed in vitro.…”

Section: N Iitro Experimentsmentioning

confidence: 48%

“…In the present study, the renal cortical Cld C, , was approximately 12 pmol/g, which also agrees well with data published by Tune and Fravert (30), who administered Cld to rabbits at 400 mg/kg sc and observed renal cortical Cld concentrations of approximately 7.5 pmoVg 30 min after dosing. In vitro, in isolated tubule fragments, this concentration would be a cytotoxic exposure to Cld (20)(21)(22). It is interesting to note that renal GSH depletion occurred at plasma concentrations above 0.1 mM (Figs.…”

Section: N Iitro Experimentsmentioning

confidence: 99%

“…Lipid peroxidation was assessed in the tissue sulfosalicylic acid supernatants as the production of malondialdehyde (MDA) according to a modification of a method described by Bernheim et a1 (2). Tissue ATP was quantitated using a bioluminescent assay (22). Samples stored in liquid nitrogen were weighed and pulverized with a mortar and pestle on dry ice.…”

Section: Bioclieniical Assaysmentioning

confidence: 99%

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Cephaloridine-Induced Renal Pathological and Biochemical Changes in Female Rabbits and Isolated Proximal Tubules in Suspension

et al. 1992

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Cephaloridine (Cld) is a nephrotoxic cephalosporin antibiotic. The intracellular biochemical changes that occur leading to Cld-induced nephrotoxicity may involve lipid peroxidation and/or mitochondria1 injury. The purpose of this report was to examine and correlate the biochemical changes induced by Cld in vivo and in vitro with the observed pathological changes in an attempt to understand better the mechanisms of@-lactaminduced nephrotoxicity. Cld treatment (500 mg/kg sc) caused elevations in blood urea nitrogen and decreases in the accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) by renal cortical slices.Histopathological alterations, characterized by individual cell necrosis of tubular epithelial cells, were first seen 6 hr after treatment in the pars recta of the outer stripe of the medulla. Ultrastructural alterations involved the straight (S, and S,) segments of the proximal tubules. Mitochondria1 morphology was, for the most part, unaffected by Cld exposure. Cld did not cause any significant changes in tissue malondialdehyde (MDA)content in vivoat any ofthe timepointsexamined, but it didcauseadepletion ofGSH toapproximately 40% of control by 1 hr after dosing that recovered toward control by 6 hr. Significant changes were observed in renal ATP content beginning at 6 hr after treatment; however, this change mirrored the onset of histological evidence of necrosis. In isolated tubules in vitro, the onset ofglutathione (GSH) depletion and MDA formation clearly preceded lactate dehydrogenase (LDH) leakage, whereas ATP depletion was a mirror image of cell death. These data demonstrate that isolated proximal tubules in vitro are a reasonable model for Cld nephrotoxicity in rivo. Cld-induced mitochondria1 alterations leading to ATP depletion and cell injury were not observed in this study.

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Section: Introduc~ionsupporting

confidence: 82%

Section: Fig 8-continuedsupporting

confidence: 54%

Section: N Iitro Experimentsmentioning

confidence: 48%

Section: N Iitro Experimentsmentioning

confidence: 99%

Section: Bioclieniical Assaysmentioning

confidence: 99%

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