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The purpose of this study was to investigate whether the tissue distribution of chlordecone (CD) and mirex (M) might explain the difference in the potentiation of CHCl3 liver injury. Male Sprague-Dawley rats received either a single oral dose of CD or M (1, 2.5, 5, 10, 25, or 50 mg/kg) or three single daily doses of CD or M (0.5, 2, or 10 mg/kg). Eighteen hours following the last treatment, the animals were divided into two groups. The first group was killed and residues of CD or M in plasma, kidney, liver, and adipose tissue were measured by gas-liquid chromatography. The other group received CHCl3 (0.5 ml/kg, po) and was killed 24 hr later. Biochemical and histological indices of liver injury were evaluated. CD administered either singly or repetitively is more effective than M in potentiating the CHCl3-induced liver injury. This was exhibited by a higher increase in the plasma activities of the enzymes alanine aminotransferase and ornithine carbamoyl transferase and a greater alteration of the morphological pattern. There was a very good correlation between biochemical and histological indices. However, the severity of the liver injury did not parallel tissue concentrations. With M, a relatively poor potentiation of the liver damage was observed although adequate hepatic concentrations were present.

A study was performed on the hepatic reaction of mice to acute intoxication with virotoxins (alaviroidin, viroisin, deoxoviroisin, viroidin, deoxoviroidin) and phalloidin, cyclic peptides isolated from Amanita virosa mushrooms. Purified fractions were administered intraperitoneally at various dosages to determine the LD50 which ranged from 1.0 to 5.3 mg/kg, with viroidin, phalloidin, and viroisin being the most potent. The virotoxins and phalloidin induced hemorrhagic necrosis of the liver. The development of hepatic lesions was followed by enhanced serum alanine aminotransferase (ALT) activity as well as by light and electron microscopic changes. In additional groups, bile ducts were cannulated and bile was collected for 2 hr after injection of the peptides (1 mg/kg) to determine their cholestatic potential. The earliest changes in hepatocytes were plasma membrane invagination and cytoplasmic vacuole formation. At later time periods, erythrocyte accumulation was evident in vacuoles and in the cytoplasm. The severity of hepatic damage, as judged by morphologic analysis, was correlated with serum ALT activity. Two of the peptides tested (viroisin and phalloidin) decreased bile flow by more than 50% over control values. Mild ultrastructural alterations in the bile canalicular pole of hepatocytes were observed during the development of cholestasis. Since virotoxins, like phalloidin, are bound to actin, it is possible that their affinity to cellular actin may be responsible for their hepatotoxicity.