Susceptibility of Heterozygous p53 Deficient CBA Mice to Induction of Liver Proliferative Lesions by Phenobarbital after Dimethylnitrosamine Initiation.

To investigate the susceptibility of heterozygous p53-deficient CBA mice [p53 (+/-) mice] to promotion of liver proliferative lesions in a two stage hepatocarcinogenesis model, 30 p53 (+/-) mice and 30 wild-type littermates [p53 (+/+) mice] received an i.p injection of 5 mg/kg of N-nitrosodimethylamine (DMN), and from one week later, each group was given free access to drinking water containing 0.05 or 0 % of phenobarbital (PB) for 26 weeks. The final body weights were significantly decreased in both p53 (+/-) and p53 (+/+) mice of the DMN+PB compared to the DMN alone groups and the liver weights were significantly increased. The survival rate was 67 and 73% in p53 (+/-) and p53 (+/+) mice of the DMN+PB group, respectively, and there were no deaths in any of the mice receiving DMN alone. The incidences of eosinophilic foci in the liver (90 and 54.6% in p53 (+/-) and p53 (+/+) mice, respectively) in the DMN+PB groups were significantly higher than those with DMN alone (6.7% in p53 (+/-) mice, 0% in p53 (+/+) mice). The incidences of clear cell foci and hepatocellular adenomas were 10.0 and 9.1%, and 60.0 and 27.3%, respectively, in p53 (+/-) and p53 (+/+) mice receiving DMN+PB. These lesions were not seen in the DMN alone group. The PCNA labeling indices for eosinophilic foci and hepatocellular adenomas in the DMN+PB group were significantly higher in p53 (+/-) than in p53 (+/+) mice. The present results suggest that p53 (+/-) CBA mice are very susceptible to promotion of the development of liver proliferative lesions by PB after DMN initiation.