Potentiation of CCl 4-induced liver injury by ketonic and ketogenic compounds: Role of the CCl 4 dose

Abstract

Potentiation of haloalkane hepatotoxicity by ketones and ketogenic agents is a well-known phenomenon. The importance of the CCl 4 dosage in these combinations, however, has not been explored. Its influence was investigated in male Sprague-Dawley rats. Dose-effect curves for potentiation were generated using 1,3-butanediol, methyl n-butyl ketone or methyl isobutyl ketone as potentiation agents. Animals were orally treated with these compounds prior to a challenge of CCl 4 (0 to 0.5 ml/kg, ip). Liver injury was assessed by monitoring plasma ALT activity and bilirubin concentrations after CCl 4 treatment. The minimal effective dosage (MED) for each potentiator was used as the criterion of comparison for each combination. The MED values were determined from the plasma ALT data. Results showed that when the CCl 4 dosage was increased from 0.01 to 0.10 ml/kg, the MED of each potentiator decreased 10-fold. For a given potentiator, the product of the CCl 4 dosage ( H, “hepatotoxicant”) by the corresponding MED value ( P, “potentiator”) remained the same in this range of CCl 4 dosages. The severity of the liver injury was similar. These findings suggest that a given level of liver injury induced by a ketone/haloalkane combination could be evaluated on the basis of the [ P × H] product.