CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice

4-Aminobiphenyl (4-ABP), a potent carcinogen in rodents (liver cancer) and human (bladder cancer), is found as an environmental contaminant and in tob acco smoke. Hemoglobin adducts and lung DNA adducts of 3-ABP are found in t obacco smokers. In vitro metabolism studies with human and rat liver micros omes have shown that CYP1A2 is primarily responsible for catalyzing N-hydro xylation, the initial step in the metabolic activation of 4-ABP, To determi ne whether this P450 is a rate limiting pathway for hepatocarcinogenesis, C YP1A2-null mice were analyzed at 16 months of age and were compared with wi ld-type mice in their response to 4-ABP using the neonatal mouse bioassay a nd two different doses of the carcinogen. Overall differences in incidences of hepatocellular adenoma, carcinoma and preneoplastic foci were not signi ficant between either genotypes or 4-ABP doses used, whereas small, but sig nificant, differences were found for specific types of foci, These results suggest that while CYP1A2 levels may not be rate limiting for 4-ABP metabol ism to produce tumors and foci, it may modulate the induction process of so me types of liver foci in either a positive or negative manner. In vitro st udies using CYP1A2-null and wild-type mouse liver microsomes revealed that CYP1A2 is not the sole P450 required for 4-ABP N-hydroxylation and that ano ther, yet to be identified, P450 is likely to be involved.