Effects of aminothiols in 2-acetylaminofluorene-treated rats. III. Metabolic activation of aromatic amines.

Six groups of Wistar rats received a standard diet supplemented with 0.05% 2-acetylaminofluorene and/or 0.1% natural (reduced glutathione) or synthetic (N-acetyl-L-cysteine) aminothiols. The discontinuous feeding regimen consisted of 4 cycles, each composed of 3 weeks of treatment followed by withdrawal for 1 week. At the 3rd and 4th week of each cycle, the liver was removed from 4-5 rats within each group, and pools of S-12 fractions were assayed for the ability to activate 2-acetylaminofluorene and other aromatic amines, either structurally related (i.e. 4-acetylaminofluorene and 2-aminofluorene) or unrelated (i.e. 2-naphtylamine and benzidine) to mutagenic metabolites in strain TA98 of S. typhimurium. In untreated rats, there was a consistent and marked trend to an age-dependent loss of metabolic activation of all test compounds during the 16 weeks of the experiment. Feeding of 2-acetylaminofluorene resulted in an evident autoinduction of metabolism which was continuously amplified with time, even during the withdrawal weeks. In the same animals, activation of the other amines was initially inhibited but then progressively shifted to a mild cross-induction which, in the case of the structurally related compounds, became significant at the end of the 4-cycle treatment with 2-acetylaminofluorene. The metabolic effects of the two aminothiols were broadly variable, depending on the thiol, on its co-administration with 2AAF, on the week and cycle of treatment, and on promutagens tested.