Effect of mixed function oxidase induction and inhibition on salicylate-induced nephrotoxicity in male rats
A previous study in this laboratory demonstrated that greater nephrotoxicity was induced by 500 mg/kg (/sup 14/C)salicylate in 12-month-old male Sprague-Dawley rats than in 3-month-old animals, and the increased nephrotoxicity was correlated with greatly increased binding of radioactivity to the renal mitochondria in the older rats. To determine the role of reactive intermediate generation in salicylate-induced nephrotoxicity, male Sprague-Dawley rats were pretreated with piperonyl butoxide, phenobarbital, or Aroclor prior to the administration of 500 mg/kg (/sup 14/C)salicylate. In the kidneys of rats pretreated with only corn oil, mitochondrial macromolecules contained 57% of the total covalently bound radioactivity while in the livers of these same animals, microsomes contained most (52%) of the bound radioactivity. Pretreatment with piperonyl butoxide, an inhibitor of mixed function oxidase activity, decreased (a) salicylate-induced nephrotoxicity; (b) the covalent binding of (/sup 14/C)salicylate equivalents to renal mitochondria; and (c) the formation of the 2,3- and 2,5-dihydroxybenoic acid metabolites of salicylate. Pretreatment with phenobarbital and Aroclor, inducers of hepatic P-450, on the other hand, had no effect on salicylate-induced nephrotoxicity nor on the covalent binding of (/sup 14/C)salicylate equivalents to renal mitochondria. These data are consistent with the hypothesis that salicylate is metabolized to reactive intermediates that irreversibly bind to renal mitochondria and lead to salicylate-induced nephrotoxicity.
- Research Organization:
- Thomas Jefferson Univ., Philadelphia, PA
- OSTI ID:
- 5229961
- Journal Information:
- Toxicol. Appl. Pharmacol.; (United States), Vol. 2
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
MIXED-FUNCTION OXIDASES
ENZYME INDUCTION
SALICYLIC ACID
TOXICITY
AGE DEPENDENCE
CARBON 14 COMPOUNDS
GLUCOSE
KIDNEYS
METABOLIC ACTIVATION
MITOCHONDRIA
PHENOBARBITAL
RATS
TRACER TECHNIQUES
ALDEHYDES
ANESTHETICS
ANIMALS
ANTICONVULSANTS
AZINES
BARBITURATES
BODY
CARBOHYDRATES
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DRUGS
ENZYMES
GENE REGULATION
HETEROCYCLIC COMPOUNDS
HEXOSES
HYDROXY ACIDS
HYPNOTICS AND SEDATIVES
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
MONOSACCHARIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANOIDS
ORGANS
OXIDOREDUCTASES
OXYGENASES
PYRIMIDINES
RODENTS
SACCHARIDES
VERTEBRATES
560305* - Chemicals Metabolism & Toxicology- Vertebrates- (-1987)