Toxicity of cephaloridine to carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria: structure-activity relationships.
Cephaloridine (Cld), the most widely studied nephrotoxic cephalosporin, has significant structural homology with carnitine, which facilitates the transport of long-chain fatty acids into the mitochondrial inner matrix. Because of this homology, and evidence of a role of lipids in cephaloglycin (Cgl) nephrotoxicity, protocols were designed to compare the effects of Cld and Cgl on renal cortical mitochondrial carnitine transport, on long-chain fatty acylcarnitine-mediated respiration and on the in situ mitochondrial pools and urinary excretion of carnitine and acylcarnitines. The following was found: 1) both cephalosporins reduced carnitine-facilitated pyruvate oxidation (CFPO) and palmitoylcarnitine-mediated respiration (PCMR) by 40 to 50% in mitochondria exposed in vivo (300 mg/kg b.wt., 1 hr). CFPO could be decreased by reduction of carnitine uptake, pyruvate oxidation or carnitine acetyltransferase activity; 2) neither cephalosporin reduced mitochondrial carnitine acetyltransferase or carnitine palmitoyltransferase; 3) with in vitro exposure (2000 micrograms/ml, immediate effect) Cgl had no significant toxicity to mitochondrial CFPO. Cld inhibited CFPO in a dose-dependent manner, up to 100% at 2000 micrograms/ml; this effect was reduced by increasing carnitine concentrations; 4) in vitro Cld prevented the potentiation of PCMR by preloading with carnitine, reduced mitochondrial acetylcarnitine/carnitine exchange by 70% and reduced PCMR by 30%; 5) in vivo Cld increased mitochondrial-free carnitine in the in situ kidney by 100%; and 6) in vivo Cld increased the fractional renal excretion of carnitine from 0 +/- 0 to 0.29 +/- 0.03 and the fractional excretion of long-chain acylcarnitines from 0.06 +/- 0.01 to 0.79 +/- 0.17.(ABSTRACT TRUNCATED AT 250 WORDS)
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D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002331:Carnitine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002509:Cephaloridine / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D011817:Rabbits; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D005227:Fatty Acids; D011773:Pyruvates; D019289:Pyruvic Acid; D002334:Carnitine O-Palmitoyltransferase; D002332:Carnitine O-Acetyltransferase; D002509:Cephaloridine; D002331:Carnitine; D010100:Oxygen