Cephaloridine is an experimental cephalosporin antibiotic that is a model proximal tubular toxin. Cephaloridine nephrotoxicity requires a sequence of events which are initiated with excessive accumulation in the proximal tubular epithelial cells. The precise mechanism for cytotoxicity is thought to involve superoxide radical formation and initiation of lipid peroxidation. Preliminary work in the principal investigator's lab has indicated that cephaloridine toxicity is reduced in streptozotocin (STZ)-induced diabetic rats. STZ-diabetic rats will be employed as an experimental probe to determine the mechanisms which confer reduced cephaloridine toxicity. The goals of this project will be accomplished through a series of experiments that will specifically determine if the mechanism for reduced toxicity is due to: a) reduced renal accumulation in STZ diabetic animals, b) increased renal excretion of cephaloridine in diabetic rats, c) cellular changes induced by a diabetic state and not STZ, d) cellular differences between normoglycemic and diabetic animals. Experiments will be conducted to investigate in vivo cephaloridine nephrotoxicity. Renal damage will be assessed following in vivo administration by quantitating: urinary parameters (volume osmolality, electrolytes, protein and glucose), kidney weight, BUN levels, serum glucose, histology and renal cortical slice accumulation of organic ions. In vitro cellular toxicity will be assessed by measuring glutathione levels and cephaloridine accumulation. The results obtained from these studies should provide a solid foundation for specifically unraveling the mechanism for reduced cephaloridine toxicity in diabetic rats. These results are also important in establishing which factors are critical for development of cephaloridine toxicity. These results may then be applicable for other nephrotoxic agents.
| Valentovic, M A; Ball, J G (1998) 2-Aminophenol and 4-aminophenol toxicity in renal slices from Sprague-Dawley and Fischer 344 rats. J Toxicol Environ Health A 55:225-40 |
| Valentovic, M A; Rogers, B A; Meadows, M K et al. (1997) Characterization of methemoglobin formation induced by 3,5-dichloroaniline, 4-amino-2,6-dichlorophenol and 3,5-dichlorophenylhydroxylamine. Toxicology 118:23-36 |
| Valentovic, M A; Ball, J G (1995) Cephaloridine nephrotoxicity in diabetic rats: modulation by insulin treatment. Toxicology 100:11-6 |
