Abstract:
:Azido-PhIP (2-azido-1-methyl-6-phenylimidazo[4,5-b]pyridine) and nitro-PhIP (2-nitro-1-methyl-6-phenylimidazo[4,5-b]pyridine) have been synthesized and characterized chemically. The mutagenic potencies of azido-PhIP (with photoactivation by near UV irradiation), of nitro-PhIP (without exogenous activation) and of the heterocyclic amine PhIP (with activation by rat liver S9) were evaluated by means of the reversion assay in Salmonella typhimurium. Like PhIP, azido- and nitro-PhIP were potent mutagens in the strain TA98. In addition to TA98, the strains YG1024 with increased and TA98/1,8-DNP6 deficient in acetyltransferase activity and TA98NR deficient in nitroreductase were used. Photolysis of azido-PhIP generates a very short-lived mutagen whose mutagenic potency is similar in all strains used and therefore not dependent on the acetyltransferase and nitroreductase. These findings are analogous to previous ones with azidofluorene and suggest that a short-lived DNA-binding arylnitrenium ion is formed directly by the photolysis of azido-PhIP. The nitroreductase contributes to the mutagenic potency of nitro-PhIP; in TA98NR it is 37% of that in TA98. The acetylator status of the strains influences the mutagenic potencies of PhIP and nitro-PhIP only weakly. This contrasts with findings obtained with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and nitro-IQ and with other amino- and nitro-imidazoarenes which lose most of their mutagenic activity in the acetyltransferase-deficient strain. This atypical behavior of PhIP suggests that the presumed metabolite, N-hydroxy-PhIP, differs from the N-hydroxy metabolites of other heterocyclic amino- and nitro-imidazoarenes in that in Salmonella it is not significantly activated by O-acetylation. It must therefore either react directly with DNA or be activated in a different way. This divergent behavior of PhIP and N-hydroxy-PhIP in Salmonella may also be a key to the understanding of several 'unusual' properties of PhIP in mammalian cells and organisms.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Wild D,Watkins BE,Vanderlaan Mdoi
10.1093/carcin/12.6.1091subject
Has Abstractpub_date
1991-06-01 00:00:00pages
1091-6issue
6eissn
0143-3334issn
1460-2180journal_volume
12pub_type
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