Inhibition of cell division in hepatoma cell cultures by chlordecone and carbon tetrachloride combination

The propensity of chlordecone (CD) to potentiate the hepatotoxic and lethal effects of CCl(4) is well established. Mirex (M), a close structural analogue of CD, or phenobarbital (PB), both powerful inducers of hepatic microsomal drug metabolizing enzymes, are much weaker potentiators of CCl(4) toxicity. Considerable evidence has accumulated to suggest that this increase in CCl(4) toxicity caused by CD is due to the failure of the hepatocellular regeneration, tissue repair and hepatolobular restoration mechanisms. This interaction occurs at concentrations of CD and CCl(4) that are individually non-toxic and do not interfere with hepatocellular division. To test this unique interaction at cellular level, we employed a rapidly dividing Reuber hepatoma cell line in vitro. Cells were pretreated with a non-toxic dose of either CD, M or PB and exposed to a single addition of CCl(4) in the concentration range 5 to 40 mm 16 days later. The results indicate that CD + CCl(4) combination specifically arrested hepatocellular division. The inhibition of cell division occurred at individually non-toxic concentrations of CD and CCl(4). M + CCl(4) or PB + CCl(4) failed to manifest similar effects. At higher concentrations, these combinations caused cellular toxicity, resulting in cell death. Suppression of cell division might play an important role in the progression of chemical-induced toxicities in the liver. This unique observation opens up new avenues to investigate biochemical molecular mechanisms underlying the interference with hepatocellular division.