Quantitative and temporal delineation of various parameters of liver dysfunction due to α-naphthylisothiocyanate

Abstract

α-Naphthylisothiocyanate (ANIT) has been found to rapidly produce liver dysfunction, viz., elevation in plasma bilirubin, sulfobromophthalein (BSP) retention, and prolongation of pentobarbital-induced loss of the righting reflex, within a relatively short time following a single oral administration of this hepatotoxic agent to mice. The 24-hour LD 50 was 245 mg/kg. The ED 50 for hyperbilirubinemia was 40 mg/kg; the ET 50 was 21 minutes. The increase in plasma bilirubin was mainly of conjugated bilirubin. The ED 50 for BSP retention was 38 mg/kg; the ET 50 was 102 minutes. The metabolized form of BSP was present in the blood stream. The ED 50 of ANIT for the prolongation of pentobarbital-induced loss of the righting reflex was 43 mg/kg, 2 hours after ANIT. Single doses of ANIT effected persistent liver dysfunction. Hyperbilirubinemia did not subside until 4 days after treatment. BSP retention was significant for 7 days and, in occasional animals, for 26 days. Prolongation of pentobarbital hypnosis was seen for 5–12 days after ANIT. The cholestatic property of ANIT was demonstrated by a direct and an indirect method. The ET 50 was 16 hours by either method. On the basis of these studies, ANIT is believed to effect liver dysfunction by a change in hepatocyte activity as well as the previously reported delayed action on bile ductules.