The mitochondrial respiratory toxicity of cephalosporin antibiotics. An inhibitory effect on substrate uptake.
Cephalosporin antibiotics can produce renal cortical mitochondrial respiratory toxicity after either in vitro or in vivo exposure. In vitro toxicity is immediate, nonselective among toxic and nontoxic cephalosporins and reversed by substrate excess. In vivo toxicity is delayed, specific to the nephrotoxic cephalosporins and not reversible. Both routes of exposure affect respiration with succinate (S) more than with glutamate plus malate as substrates. Because glutamate and malate gain access to the intramitochondrial electron transport chain proximal to S, this pattern suggests that the cephalosporins affect a mitochondrial function outside the respiratory chain. A model of respiratory toxicity incorporating all of these features proposes that all cephalosporins can fit the affected transporters for mitochondrial substrate uptake, but, in the intact kidney, this causes limited or transient respiratory inhibition with nontoxic cephalosporins; in vivo toxicity, which is seen after later isolation and washing of mitochondria exposed in situ, develops with the more sequestered and reactive (nephrotoxic) cephalosporins that acylate these transporters. As a test of this hypothesis, studies were done, using the method of sieve filtration, to evaluate the effects of in vivo and in vitro exposure to cephaloglycin (toxic) and cephalexin (nontoxic) on the uptake of S and ADP by rabbit renal cortical mitochondria. In vivo and in vitro exposure to cephaloglycin reduced the net uptake of S by 70% and had a considerably smaller and less consistent effect on ADP uptake; cephalexin inhibited S uptake only with in vitro exposure. The rate of S washout from cephaloglycin-intoxicated mitochondria was no greater than from controls, ruling out increased efflux as a cause of decreased net uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Tune
B M
BM
Department of Pediatrics, Stanford University School of Medicine, California.
Sibley
R K
RK
Hsu
C Y
CY
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002511:Cephalosporins / Q000633:toxicity*; D005260:Female; D005615:Freezing; D007668:Kidney / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects*; D011817:Rabbits; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid
D002511:Cephalosporins; D013386:Succinates; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000244:Adenosine Diphosphate; D019802:Succinic Acid