Perturbations in polyamines and related enzymes following chlordecone-potentiated bromotrichloromethane hepatotoxicity

The mechanism by which chlordecone (CD) amplifies the hepatotoxicity of halomethanes such as CCl₄, CHCl₃, and BrCCl₃ has been a subject of intense study. Recent work has shown that suppression of hepatocellular regeneration leads to accelerated progression of liver injury leading to complete hepatic failure due to an unusual interaction between individually nontoxic low-dose combination of CD and CCl₄. Since polyamines are involved in cell division, their levels reflect the extent to which there is suppression of hepatocellular regeneration during CD and CCl₄ interaction. The present studies were designed to investigate the polyamine levels and associated enzymes in livers of rats treated with BrCCl₃ alone or CD and BrCCl₃ low-dose combination in order to confirm whether the sequence of events of hepatotoxicity is similar to that seen in CCl₄ toxicity or that seen during CD and CCl₄ interaction. The extent of liver toxicity in rats fed 10 ppm chlordecone (CD) for 15 days prior to the injection of a single low dose of BrCCl₃ (15 μL/kg body weight) or after exposure to a high dose of BrCCl₃ (80 μL/kg body weight) without CD pretreatment, was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was also an increase in transaminase levels, in rats exposed to a single low dose of BrCCl₃ alone (15 μL/kg body weight) but this increase was far below the high-dose exposure alone or the combination treatment. Hepatic levels of ornithine decarboxylase, S-adeno-sylmethionine decarboxylase, N¹-acetylputrescine, N¹-acetylspermidine, putrescine, spermidine, and spermine at the end of 24 hr increased after exposure to a low dose of BrCCl₃ alone as compared to exposure to a high dose alone or the low-dose combination of CD and BrCCl₃. Liver spermidine N¹-acetyltrans-ferase was elevated at 2, 6, and 24 hr after exposure to a high dose of BrCCl₃ alone as compared to treatment with a low-dose combination of CD and BrCCl₃ suggesting decreased synthesis of this enzyme, in spite of a greater need as seen from liver transaminase levels. In general, it was observed that there is significant elevation in some polyamines and related enzymes during toxicity of a low dose of BrCCl₃ which seemed to stabilize within 24 hr. This was not observed with the other two groups of rats exposed either to BrCCl₃ high dose alone or the low-dose combination of CD and BrCCl₃. Results indicate that CD and BrCCl₃ low-dose combination treatment causes increased liver toxicity resulting in compromised polyamine metabolism which is coincidental with suppressed hepatocellular regeneration leading to accelerated progressive phase of liver injury culminating in complete hepatic failure. These findings point to the possibility that the mechanism of potenti-ation of BrCCl₃ hepatotoxicity by CD is similar to that seen for CD and CCl₄ interaction.