Liver tumor-promoting effect of beta-naphthoflavone, a strong CYP 1A1/2 inducer, and the relationship between CYP 1A1/2 induction and Cx32 decrease in its hepatocarcinogenesis in the rat

Interrelationships among induction of cytochrome P-450 (CYP) 1A1/2, decreas e in connexin 32 (Cx32), and liver tumor-promoting activity by beta-naphtho flavone (BNF) in the promotion stage were examined in a 2-stage liver carci nogenesis model. A total of 20 male Fischer 344 rats were initiated with a single intraperitoneal injection of 150 mg/kg of diethylnitrosamine (DEN) o r were given the saline vehicle alone. Starting 2 weeks later, they were fe d a diet containing 2%, 1%, or 0% BNF for 6 weeks. All animals were subject ed to a two-thirds partial hepatectomy at week 3 and were sacrificed at wee k 8. Absolute and relative liver weights were significantly increased in th e DEN+BNF groups as compared to the DEN-alone group. Diffuse hepatocellular hypertrophy with cytoplasmic eosinophilia, sometimes accompanied by develo pment of adenoma-like hepatic foci, was observed in the BNF-treated rats. R emarkable induction of cytochrome CYP 1A1/2 and significant increase in CYP 2E1 were noted in the DEN+BNF groups, and positive immunohistochemical sta ining for both was observed diffusely. The areas of Cx32-positive spots per hepatocyte in the centrilobular areas of livers of the BNF-treated rats we re significantly decreased, but no changes were observed in periportal area s. The numbers and areas of foci positive for glutathione S-transferase pla cental form were increased in the BNF-treated groups. These results suggest that BNF is a liver tumor promoter that, unlike phenobarbital, does not in duce CYP 2B1/2 isozymes, and there seems to be no direct relationship betwe en CYP 1A1/2 induction and Cx32 reduction in BNF hepatocarcinogenesis.