PubMed1986
Mutagenic heterocyclic amines are metabolized to mutagens which act directly on Salmonella typhimurium by P-448 forms of cytochrome P-450. These direct mutagens are N-hydroxylated heterocyclic amines, such as N-hydroxy-Trp-P-1, N-hydroxy-Trp-P-2, N-hydroxy-Glu-P-1, N-hydroxy-Glu-P-2, N-hydroxy-IQ, N-hydroxy-2-amino-alpha-carboline (N-hydroxy-A alpha C), and N-hydroxy-2-amino-3-methyl-alpha-carboline (N-hydroxy-MeA alpha C). The treatment of rats with polychlorinated biphenyl stimulated N-hydroxylation of heterocyclic amines about 10- to 260-fold depending on the substrates used. The N-hydroxylation activities of purified cytochrome P-448-H and P-448-L were markedly different. P-448-H, which had very low activity for benzo[a] pyrene metabolic activation, showed high N-hydroxylation activity. The activity ratio P-448-H:P-448-L was markedly different depending on the amines used. This ratio was 45, 22, 3, and 0.02, respectively, for Glu-P-1, IQ, Trp-P-2, and benzo[a] pyrene. On the other hand, N-acetylation of the heterocyclic amines was very low. Although marked species differences in the N-acetylation were observed, the activities of the heterocyclic amines were about 1/100 of that of 2-aminofluorene. N-Hydroxy-Trp-P-2 could react directly to DNA, but N-hydroxy-Glu-P-1 could not. Therefore we need to consider the presence of a further activating system in mammalian and bacterial cells. We observed that N-hydroxy-Trp-P-2 was activated by prolyl-t-RNA synthetase, but N-hydroxy-Glu-P-1 was not activated by the same system. In the bacterial cells, both N-hydroxy-Trp-P-2 and N-hydroxy-Glu-P-1 were not activated by prolyl-t-RNA synthetase. However, both hydroxylamines were activated by the acetyl-CoA-dependent mechanism in mammalian and bacterial cells. These results indicated that the O-acetylation is an important pathway for DNA damage by heterocyclic amines in chemical carcinogenesis.