Decrease in the Metabolic Activating Capacities of Arylamines in Livers Bearing Hyperplastic Nodules: Association with the Selective Changes in Hepatic P‐450 Isozymes

The mechanism of the alteration in carcinogenic arylamine‐activating capacities in livers bearing pre‐neoplastic (or hyperplastic) nodules induced by the Solt‐Farber protocol was investigated in relation to the changes in hepatic cytochrome P‐450 isozymes. In the Salmonella mutagenesis test, the numbers of revertants induced with 2‐amino‐3‐methylimidazo[4,5‐ f ]quinoline and 2‐aminofluorene were significantly lower in the presence of microsomes of nodule‐bearing livers than of control livers. A similar tendency was also observed with another heterocyclic arylamine, 2‐amino‐6‐methyldipyrido‐[1,2‐ a :3′,2′‐d]imidazole. In Western blots using specific antibodies against 5 different forms of cytochrome P‐450, hepatic contents of P‐450‐male (a main constitutive form) and P‐450b (a main phenobarbital‐inducible form) were decreased in the livers with hyperplastic nodules to 63% and 35% of the corresponding controls, while no significant decrease was observed in the contents of P‐448‐H (a main 3‐methylcholanthrene‐inducible form), P‐450 6β‐1 (testosterone 6β‐hydroxylase) and P‐450e (a phenobarbital‐inducible form). In accordance with the reduction in P‐450‐male, capacities for microsomal 16α‐ and 2α‐hydroxylations, but not 6β‐hydroxylation, of testosterone were decreased in the livers with hyperplastic nodules. Although P‐448‐H has higher capacities for the activation of arylamines than does P‐450‐male, the hepatic content of P‐450‐male is more than ten‐fold higher than that of P‐448‐H in both normal and nodule‐bearing livers. These results indicate that the selective decrease in hepatic content of P‐450‐male is likely to be a main cause of the decrease in arylamine metabolic activating capacities in livers with hyperplastic nodules.