IN-VIVO ADMINISTRATION OF DICHLOROACETIC ACID SUPPRESSES SPONTANEOUS APOPTOSIS IN MURINE HEPATOCYTES

Spontaneous apoptosis in hepatocytes of male B6C3F1 mice that received dichloroacetic acid (DCA) in their drinking water for 5-30 days (28-5 8 days of life) was examined as part of ongoing studies to determine t he molecular basis of the hepatocarcinogenicity of this nongenotoxic w ater chlorination by-product, DCA at 0.5 and 5.0 g/liter, significantl y reduced apoptosis relative to untreated controls in a dose-dependent fashion. Regression analysis indicated that apoptosis declined over t he 30-day period in the livers of control, age-paired animals receivin g no drug. Animals receiving low-dose DCA exhibited a similar, althoug h 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 su ggest that DCA has the ability to down-regulate apoptosis in murine li ver. When taken together with previous data demonstrating DCA-dependen t decrease in labeling index in these same livers, these data further support the hypothesis that the carcinogenic mechanism of DCA may invo lve suppression of the ability of the liver to remove initiated cells by apoptosis rather than by induction of selective proliferation of in itiated cells.