The mechanism of hepatotoxicity of a chromone carboxylic acid (FPL 52757) in the dog.

1. The chromone carboxylic acid (6,8-diethyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid) is hepatotoxic in dogs (at 40 mg/kg per day). This toxicity did not appear to be mediated by a reactive metabolite, as the compound was not metabolized by the dog, and phenobarbitone pretreatment (20 mg/kg per day) protected rather than potentiated. 2. Other studies in the dog showed that the chromone caused increases in the biliary excretion of alkaline phosphatase (17-fold), gamma-glutamyl-transpeptidase (9-fold), and 5'-nucleotidase (13-fold) which paralleled the biliary concentration of the drug (up to 1.3 mg/ml) and was accompanied by a reduction in bile flow. 3. The excretion of the chromone into the biliary tract of the dog was shown to be saturable, and therefore high hepatocellular concentrations of the drug and subsequent liver damage could result. 4. The toxicity of the chromone when administered to rat by retrograde biliary infusion, and the lysis of erythrocytes in vitro, are related to detergent properties of the drug and add confirmatory evidence for a mechanism of toxicity in the dog. 5. It is concluded that the chromone itself is responsible for the toxicity in the dog due to its detergent properties causing damage to the hepatobiliary tract. The protection by phenobarbitone and also by methionine may have been due to an increased bile flow reducing biliary concentrations.