Biochemical mechanisms of cephaloridine nephrotoxicity.
Large doses of the cephalosporin antibiotic, cephaloridine, produce acute proximal tubular necrosis in humans and in laboratory animals. Cephaloridine is actively transported into the proximal tubular cell by an organic anion transport system while transport across the lumenal membrane into tubular fluid appears restricted. High intracellular concentrations of cephaloridine are attained in the proximal tubular cell which are critical to the development of nephrotoxicity. There is substantial evidence indicating that oxidative stress plays a major role in cephaloridine nephrotoxicity. Cephaloridine depletes reduced glutathione, increases oxidized glutathione and induces lipid peroxidation in renal cortical tissue. The molecular mechanisms mediating cephaloridine-induced oxidative stress are not well understood. Inhibition in gluconeogenesis is a relatively early biochemical effect of cephaloridine and is independent of lipid peroxidation. Furthermore, cephaloridine inhibits gluconeogenesis in both target (kidney) and non-target (liver) organs of cephaloridine toxicity. Since glucose is not a major fuel of proximal tubular cells, it is unlikely that cephaloridine-induced tubular necrosis is mediated by the effects of this drug on glucose synthesis.
Goldstein
R S
RS
Smith Kline & French Laboratories, Department of Investigative Toxicology, King of Prussia, PA 19406-0939.
Smith
P F
PF
Tarloff
J B
JB
Contardi
L
L
Rush
G F
GF
Hook
J B
JB
D000818:Animals; D001692:Biological Transport; D002509:Cephaloridine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005943:Gluconeogenesis; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology
D008054:Lipid Peroxides; D003577:Cytochrome P-450 Enzyme System; D002509:Cephaloridine