The time course of liver injury and [3H]thymidine incorporation in chlordecone-potentiated CHCl3 hepatotoxicity.

The mechanism by which chlordecone (CD) potentiates CHCl3 hepatotoxicity and lethality remains unknown. We examined the time course of the hepatotoxicity by following serum enzymes, liver histopathology, hepatocellular regeneration, and tissue repair by morphometric analysis and [3H]thymidine (3H-T) incorporation into nuclear DNA. Male mice fed control, or CD (10 ppm), mirex (Mx. 10 ppm), or phenobarbital (PB. 225 ppm) diets for 15 days and receiving a single ip dose of 0.1 ml CHCl3/kg in corn oil vehicle were used. Liver damage was assessed by plasma alanine and aspartate transaminases and by histopathology at 4, 12, 24, 36, 48, 72, and 96 hr after CHCl3 administration. None of the dietary pretreatments caused plasma transaminase elevations, any liver necrosis, or any increase in 3H-T incorporation in nuclear DNA at any time. CHCl3 alone caused only limited hepatocellular necrosis without any increase in plasma transaminases. The same dose of CHCl3 given to CD-pretreated mice resulted in greatly increased liver injury. Plasma transaminases were elevated starting at 4 hr, reaching a maximum value at 12 hr and a decline starting at 48 hr. Centrilobular and midzonal necroses were evident at 12 hr onward. PB pretreatment caused some increase in CHCl3-induced necrosis and a moderate rise in transaminases at 24 hr, but Mx pretreatment caused neither effect. 3H-T incorporation was increased at 72 and 96 hr after CHCl3 alone. The same dose of CHCl3 caused only a modest increase in PB and Mx and a significant and maximal biphasic increase at 36 and 72 hr CD-pretreated mice. Morphometry of liver sections indicated that hepatocellular regeneration is stimulated at 72 hr after CHCl3 alone. The same dose of CHCl3 results in a greater stimulation of hepatocellular regeneration in CD-pretreated mice, and this event is pushed forward at 48 hr, continuing through 96 hr to compensate for greater hepatocellular necrosis associated with this treatment. Lesser stimulation of hepatocellular regeneration was observed in PB + CHCl3 and Mx + CHCl3 groups of mice consonance with much lesser hepatotoxicity. These results suggest that the critical decisive event in the recovery from limited hepatocellular injury is the hepatocellular regeneration and tissue repair, which appear to be stimulated in proportion to the injury.