Metabolism of N-hydroxy-2-acetylaminofluorene and N-hydroxy-2-aminofluorene by guinea pig liver microsomes.

The guinea pig is resistant to the hepatocarcinogenic effects of 2-acetylaminofluorene and 2-aminofluorene. This resistance, however, is not due to the lack of a N-hydroxylating enzyme in the liver which catalyzes the first and rate-limiting step to the activation of these chemicals to proximal carcinogens. It is shown that guinea pig liver microsomes can N-hydroxylate both of these compounds. The N-hydroxylation of 2-acetylaminofluorene but not 2-aminofluorene is inducible by pretreating the guinea pigs with benz(a)anthracene. The microsomal reaction is inhibited by 3-methylcholanthrene, miconazole, or 7,8-benzoflavone, 7-Iodo-2-acetylaminofluorene is N-hydroxylated by guinea pig liver microsomes at approximately the same rate as 2-acetylaminofluorene. The N-hydroxylation of 7-fluoro-2-acetyl-aminofluorene occurs at a much faster rate. The resistance of the guinea pig liver to the carcinogenic effect of the arylamides and arylamines may actually be due to the ability to further convert the N-hydroxylated metabolites to the inactive C7-hydroxylated product. The conversion of N-hydroxy-2-acetylaminofluorene to C7-hydroxy-2-acetylaminofluorene by guinea pig liver microsomes is inhibited by 8-hydroxyquinoline or miconazole. The microsomal metabolic activation of the 7-iodo-2-acetylaminofluorene used to confirm this new metabolic pathway proceeds via a deacetylation step which could explain the resistance of the rat to the carcinogenic effect of that chemical. The high yield of the N-hydroxy-7-fluoro-2-acetylaminofluorene produced by liver microsomes could be responsible for its high carcinogenic potency.