The Effect of Prior Dosing with Phenobarbitone and β-Diethylaminoethyl Diphenylpropyl Acetate (SKF525A) on the Toxicity and Liver Lesion Caused by Ngaione in the Mouse

Evidence is presented that the sesquiterpene essential oil ngaione needs metabolism in the liver for hepatotoxicity in mice. Prior treatment with SKF525A caused an increase in the LD₅₀ from 0·28 to 0·53 g/kg body weight. Paradoxically, however, pretreatment with phenobarbitone also caused an increase in the LD₅₀ to 0·37 g/kg body weight. The location of the zonal liver lesion due to ngaione, namely confluent midzonal in controls, could be consistently varied with induced alterations in the level of the hepatic mixed function oxidases in that with prior dosing with SKF525A the lesion was centrilobular, while in phenobarbitone treated mice it was periportal. These effects returned to the control state by 4 days after the respective pretreatment by which time hepatic microsomal enzyme activity was also normal.The observations suggest a pathogenetic mechanism for the rare lesion, confluent midzonal necrosis due to ngaione in this species based on graded efficiency of metabolism of the agent across the hepatocytes of the liver acinus.