Mitochondrial cytochrome c oxidase as a target site for cephalosporin antibiotics in renal epithelial cells (LLC-PK(1)) and renal cortex.
We reported previously that treatment of the pig kidney proximal tubular epithelial cell line LLC-PK(1) with cephaloridine (CLD) decreased the activity of cytochrome c oxidase in the mitochondria of the cells followed by increases in lipid peroxidation and cell necrosis. In this study, we investigated the effects of CLD on the activity of cytochrome c oxidase in mitochondria isolated from LLC-PK(1) cells and purified the enzyme from mitochondria of the rat renal cortex. The activity of cytochrome c oxidase in the isolated mitochondria from LLC-PK(1) cells was significantly decreased from 1 h after addition of 1 mM CLD. Other cephalosporin antibiotics, cefazolin and cefalotin, also decreased the activity of cytochrome c oxidase in the isolated mitochondria. The activity of cytochrome c oxidase purified from the mitochondria of the rat renal cortex was also decreased from 2 h after addition of 1 mM CLD in a non-competitive manner. These results suggest that the direct inhibition of cytochrome c oxidase activity in the mitochondrial electron transport chain by cephlosporins may result from the observed nephrotoxicity.
Kiyomiya
Ken-ichi
K
Laboratory of Toxicology, Graduate School of Veterinary Medicine, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan. kiyomiya@vet.osakafu-u.ac.jp
Matsushita
Naoko
N
Kurebe
Masaru
M
Nakagawa
Hiroshi
H
Matsuo
Saburou
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D002509:Cephaloridine / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D003576:Electron Transport Complex IV / Q000302:isolation & purification / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007672:Kidney Cortex / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D024101:Mitochondrial Proteins; D003576:Electron Transport Complex IV; D002509:Cephaloridine