In Vivo Administration of Dichloroacetic Acid Suppresses Spontaneous Apoptosis in Murine Hepatocytes1

Spontaneous apoptosis in hepatocytes or male B6C3F1 mice that re ceived dichloroacetic acid (DCA) in their drinking water for 5-30 days (28-58 days of life) was examined as part of ongoing studies to determine the molecular basis of the hepatocarcinogenicity of this nongenotoxic water chlorination by-product. DCA at 0.5 and 5.0 g/liter, significantly reduced apoptosis relative to untreated controls in a dose-dependent fashion. Regression analysis indicated that apoptosis declined over the 30-day period in the livers of control, age-paired animals receiving no drug. Animals receiving low-dose DCA exhibited a similar, although quantitatively depressed, trend line, whereas animals receiving high-dose DCA showed maximal depression of apoptosis at 5 days, which was sustained throughout the course of the 30-day period. These studies suggest that DCA has the ability to down-regulate apoptosis in murine liver. When taken together with previous data demonstrating DCA-dependent decrease in labeling index in these same livers, these data further support the hypothesis that the carcinogenic mechanism of DCA may involve suppression of the ability of the liver to remove initiated cells by apoptosis rather than by induction of selective proliferation of initiated cells.