TOXICITY OF CEPHALOSPORINS TO FATTY-ACID METABOLISM IN RABBIT RENAL CORTICAL MITOCHONDRIA

Cephaloglycin (Cgl) and cephaloridine (Cld) are acutely toxic to the p roximal renal tubule, in part because of their cellular uptake by a co ntraluminal anionic secretory carrier and in part through their intrac ellular attack on the mitochondrial transport and oxidation of tricarb oxylic acid (TCA) cycle anionic substrates. Preliminary studies with C gl have provided evidence of a role of fatty acid (FA) metabolism in i ts nephrotoxicity, and work with Cld has shown it to be a potent inhib itor of renal tubular cell and mitochondrial carnitine (Carn) transpor t. Studies were therefore done to examine the effects of Cgl and Cld o n 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 mitochondr ion by the Carn shuttle. The following was found: (1) Cgl reduced the oxidation and uptake of butyrate after in vitro (2000 mu g/mL, immedia te effect) and after in vivo (300 mg/kg body weight, 1 hr before killi ng) exposure; (2) Cld caused milder in vitro toxicity, and no signific ant in vivo toxicity, to mitochondrial butyrate metabolism; (3) like C ld, Cgl reduced PCarn-mediated respiration after in vivo exposure, but , unlike Cld, it did not inhibit respiration with PCarn in vitro; (4) the Cam carrier was stimulated slightly by in vitro Cgl but was unaffe cted by in vivo Cgl; (5) in vivo Cgl had no effect on mitochondrial fr ee Carn or long-chain acylCarn concentrations in the in situ kidney; ( 6) Cgl increased the excretion of Carn minimally compared with the eff ect of Cld; and (7) cephalexin, a nontoxic cephalosporin, caused mild reductions of respiration with butyrate and PCarn during in vitro expo sure, but stimulated respiration with both substrates after in vivo ex posure. Conclusions: Cgl has essentially the same patterns of in vitro and in vivo toxicity against mitochondrial butyrate uptake and oxidat ion that both Cgl and Cld have against TCA-cycle substrates. Cld has l ittle or no in vivo toxicity to mitochondrial butyrate metabolism, whe reas in vivo Cgl is as toxic as Cld to respiration with PCarn. The gre ater overall in vivo toxicity of Cgl to mitochondrial FA metabolism, w ith lower cortical concentrations and AUCs than those of Cld, supports earlier evidence that Cld is less toxic than Cgl at the molecular lev el.