Amplified response to phenobarbital promotion of hepatotumorigenesis in obese yellow Avy/A (C3H x VY) F-1 hybrid mice.

Abstract

Mottled yellow Avy/A and agouti A/a (C3H x VY) F-1 hybrid male mice were fed untreated control diet or diet with a target dose of 500 p.p.m. sodium phenobarbital (PB) for 17-19 months. No differences in prevalence of hepatocellular adenomas or carcinomas were found between untreated yellow and agouti mice. PB treatment increased prevalence of adenomas but decreased prevalence of carcinomas. No difference in enhancement of adenoma formation by PB was observed between yellow and agouti mice bearing single adenomas. However, the proportion of PB-treated yellow mice bearing multiple adenomas (66%) was much greater than the proportion of analogous agouti mice (18%). Fatty changes in the periportal area of the liver and focal cytoplasmic vacuolization were induced to a much greater extent in PB-treated yellow mice than among treated agoutis. PB increased the prevalence and severity of focal areas of chronic inflammation in the liver considerably more in agouti than in yellow mice. The possible relation of this finding to the altered immune responses of obese yellow mice remains to be determined. The results of this study suggest that the use of yellow Avy/A and agouti A/a (C3H x VY) F-1 hybrid mice in carcinogenicity assays make make it possible to differentiate between weak and strong promoters as well as between promoters and complete carcinogens. Weak promoters should induce hepatocellular adenomas in yellow mice even if they fail to do so in agouti mice. Promoting substances which act similarly to PB may be identified in this system by simultaneously increasing adenoma prevalence and decreasing carcinoma prevalence. Complete carcinogens should increase carcinoma prevalence in the yellow mice even at low dose levels.