The renal mitochondrial toxicity of cephalosporins: specificity of the effect on anionic substrate uptake

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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes

Published on: January 7, 2013

B M Tune1, C Y Hsu

  • 1Department of Pediatrics, Stanford University School of Medicine, California.

The Journal of Pharmacology and Experimental Therapeutics
|January 1, 1990
PubMed

Insights

Nephrotoxic beta-lactam antibiotics, like cephaloridine, impair renal mitochondrial function by reducing succinate uptake and respiration. This effect is specific to the kidney and not observed with non-nephrotoxic antibiotics.

Area of Science:

  • Nephrology
  • Mitochondrial Biology
  • Pharmacology

Background:

  • Nephrotoxic beta-lactam antibiotics reduce renal mitochondrial uptake and respiration of succinate.
  • The causal relationship between reduced substrate uptake and decreased respiration requires further investigation.

Purpose of the Study:

  • To test the hypothesis that reduced substrate uptake and decreased mitochondrial respiration are causally linked.
  • To examine the specificity of this association in renal mitochondria following cephalosporin insult.
  • To investigate the involvement of carrier-mediated anionic substrate transport.

Main Methods:

  • Utilized rabbits to study the effects of cephaloridine on renal mitochondria.
  • Compared cephaloridine with the non-nephrotoxic cephalexin.
  • Investigated the impact of acute renal artery occlusion and respiratory toxins (cyanide, oligomycin) on mitochondrial function.
  • Assessed cephaloridine's effect on hepatic mitochondria.

Main Results:

  • Cephaloridine significantly reduced succinate uptake and respiration in renal mitochondria.
  • The non-nephrotoxic cephalexin had no such effect.
  • Renal artery occlusion reduced succinate uptake and respiration but increased substrate efflux.
  • Cyanide and oligomycin inhibited respiration directly without affecting substrate uptake.
  • Cephaloridine did not affect succinate uptake or respiration in hepatic mitochondria.

Conclusions:

  • Reduced succinate uptake is specifically associated with the nephrotoxic effects of cephalosporins on renal mitochondria.
  • The observed reduction in respiration is linked to impaired substrate transport, not direct mitochondrial toxicity.
  • Cephaloridine's nephrotoxicity is organ-specific to the kidneys.

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