Early induction of reparative hyperplasia in the liver of B6C3F1 mice treated with dichloroacetate and trichloroacetate.
Trichloroacetate (TCA) and dichloroacetate (DCA) were administered at concentrations of 0, 300, 1000 or 2000 mg/l in the drinking water of male B6C3F1 and male and female Swiss-Webster mice for up to 14 days. At 2, 5 or 14 days of treatment, mice were injected with [3H]thymidine 2 h prior to sacrifice. The livers were examined histologically and autoradiographically and DNA was isolated and counted. As observed in chronic studies dichloroacetate induced a marked increase in liver weights, but only after 14 days of treatment and local necrosis in both B6C3F1 and Swiss-Webster mice. A significant increase in the labeling index of hepatocytes was observed in animals treated with DCA, but only at 14 days of treatment. No such increases were observed in animals treated with TCA. In contrast, significant increases in [3H]thymidine were observed in the livers of both DCA- and TCA-treated animals after 5 days of treatment. This effect remained apparent with TCA after 14 days of treatment. These data support the hypothesis that the tumorigenic effect of DCA is strongly influenced by necrosis and reparative hyperplasia. On the other hand, the carcinogenic effects of TCA appear to be more closely associated with [3H]thymidine incorporation that can be separated from cell division, suggesting an elevated rate of repair synthesis of DNA. Thus the carcinogenic effects of TCA (and perhaps lower doses of DCA) may involve damage to DNA.
Sanchez
I M
IM
Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman 99164-6510.
Bull
R J
RJ
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D003999:Dichloroacetic Acid / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D014238:Trichloroacetic Acid / Q000633:toxicity*
D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid