Mechanism of the mitochondrial respiratory toxicity of cephalosporin antibiotics.

Abstract

In summary, cephaloglycin, a nephrotoxic cephalosporin, produces a specific pattern of mitochondrial toxicity, decreasing both respiration with and the net uptake of succinate in renal cortical mitochondria after either in vivo or in vitro exposure, with no effect on succinate efflux. There is little or no reduction of ADP uptake by the same toxic exposures. Cephalexin, which is not toxic in vivo, inhibits respiration and uptake only with in vitro exposure. Fragmentation of mitochondria, which allows access of succinate to intramitochondrial enzymes without the need for carrier-mediated uptake, partially corrects the respiratory toxicity of cephaloglycin. We conclude that cephalosporin toxicity to succinate transport parallels the pattern of injury to mitochondrial respiration and may be pathogenic in this respiratory toxicity. These observations are consistent with the hypothesis that a) both nephrotoxic and nontoxic cephalosporins can fit the carriers for mitochondrial anionic substrate transport, and b) in situ nephrotoxicity develops as inhibition of transport becomes irreversible through acylation of these carriers.