Toxicity of cephalosporins to fatty acid metabolism in rabbit renal cortical mitochondria.
Cephaloglycin (Cgl) and cephaloridine (Cld) are acutely toxic to the proximal renal tubule, in part because of their cellular uptake by a contraluminal anionic secretory carrier and in part through their intracellular attack on the mitochondrial transport and oxidation of tricarboxylic acid (TCA) cycle anionic substrates. Preliminary studies with Cgl have provided evidence of a role of fatty acid (FA) metabolism in its nephrotoxicity, and work with Cld has shown it to be a potent inhibitor of renal tubular cell and mitochondrial carnitine (Carn) transport. Studies were therefore done to examine the effects of Cgl and Cld on the mitochondrial metabolism of butyrate, the anion of a short-chain FA that does not require the Carn shuttle to enter the inner matrix, and the effects of Cgl on the metabolism of palmitoylcarnitine (PCarn), the Carn conjugate of a long-chain FA that does enter the mitochondrion by the Carn shuttle. The following was found: (1) Cgl reduced the oxidation and uptake of butyrate after in vitro (2000 micrograms/mL, immediate effect) and after in vivo (300 mg/kg body weight, 1 hr before killing) exposure; (2) Cld caused milder in vitro toxicity, and no significant in vivo toxicity, to mitochondrial butyrate metabolism; (3) like Cld, Cgl reduced PCarn-mediated respiration after in vivo exposure, but, unlike Cld, it did not inhibit respiration with PCarn in vitro; (4) the Carn carrier was stimulated slightly by in vitro Cgl but was unaffected by in vivo Cgl; (5) in vivo Cgl had no effect on mitochondrial free Carn or long-chain acylCarn concentrations in the in situ kidney; (6) Cgl increased the excretion of Carn minimally compared with the effect of Cld; and (7) cephalexin, a nontoxic cephalosporin, caused mild reductions of respiration with butyrate and PCarn during in vitro exposure, but stimulated respiration with both substrates after in vivo exposure.


CONCLUSIONS
Cgl has essentially the same patterns of in vitro and in vivo toxicity against mitochondrial butyrate uptake and oxidation that both Cgl and Cld have against TCA-cycle substrates. Cld has little or no in vivo toxicity to mitochondrial butyrate metabolism, whereas in vivo Cgl is as toxic as Cld to respiration with PCarn. The greater overall in vivo toxicity of Cgl to mitochondrial FA metabolism, with lower cortical concentrations and AUCs than those of Cld, supports earlier evidence that Cld is less toxic than Cgl at the molecular level.
Tune
B M
BM
Department of Pediatrics, Stanford University School of Medicine, CA 94305-5119.
Hsu
C Y
CY
D000818:Animals; D002087:Butyrates / Q000378:metabolism; D020148:Butyric Acid; D002331:Carnitine / Q000378:metabolism* / Q000652:urine; D002506:Cephalexin / Q000633:toxicity; D002507:Cephaloglycin / Q000633:toxicity; D002509:Cephaloridine / Q000633:toxicity; D002511:Cephalosporins / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010172:Palmitoylcarnitine / Q000378:metabolism; D011817:Rabbits
D002087:Butyrates; D002511:Cephalosporins; D005227:Fatty Acids; D020148:Butyric Acid; D010172:Palmitoylcarnitine; D002509:Cephaloridine; D002507:Cephaloglycin; D002506:Cephalexin; D002331:Carnitine