Biochemical basis for the resistance of guinea-pig and monkey to the carcinogenic effects of arylamines and arylamides

Abstract

1. A g.l.c. assay for N-hydroxy-2-acetamidofluorene has been modified to measure both N-hydroxy-2-acetamidofluorene and N-hydroxy-2-aminofluorene.

2. Like guinea-pig, monkey N-hydroxylates both 2-aminofluorene and 2-acetamido-fluorene. The N-hydroxy metabolites are rapidly further metabolized even in the presence of inhibitors of deacetylase. The exact nature of this further metabolism is still unknown. Preliminary evidence indicates that, at least in the guinea-pig, 7-hydroxy-2-acetamidofluorene may be a metabolite of N-hydroxy-2-acetamidofluorene.

3. 3-Methylcholanthrene, 7,8-benzoflavone and miconazole, which have been shown to inhibit guinea-pig liver microsomal N-hydroxylase, do not significantly inhibit the monkey liver enzyme.

4. 2-Acetamidofluorene, which inhibits the guinea-pig liver microsomal N-hydroxylation of 2-aminofluorene in vitro, activates the enzyme from monkey liver. This activation, which is dose-dependent, appears to be allosteric.

5. Both guinea-pig and monkey arc more efficient in N-hydroxylating 2-aminofluorene than 2-acetamidofluorene. The affinity (in term of apparent K_M) of the guinea-pig liver enzyme is 4 times greater than the affinity of the monkey liver enzyme.