Metabolism of 2-acetylaminofluorene in the Chinese hamster ovary cell mutation assay
Chinese hamster ovary (CHO) cells were exposed to 2-acetylaminofluorene (2-AAF) and 2-aminofluorene (2-AF), and several of their N-oxidized metabolites in order to study the mechanisms by which arylamides and arylamines produce mutations in mammalian cells. The number of mutations induced at the hypoxanthine-guanine phosphoribosyl transferase locus by each compound was estimated to be: N-acetoxy-2-AAF, 310; N-hydroxy-2-AF, 3; N-hydroxy-2-AAF, 0.7; 2-AAF, 0.1; and 2-AF, 0.09. With each compound, DNA adducts were also identified and quantified, and in all cases the major adduct was N-(deoxyguanosin-8-yl)-2-AF. The relationship between mutation induction and adduct formation for each of the derivatives was similar to that previously reported for N-hydroxy-2-AF. Inclusion of the deacetylase inhibitor, paraoxon, reduced the mutagenicity of 2-AFF, N-hydroxy-2-AAF and N-acetoxy-2-AAF, and the DNA adducts produced by N-acetoxy-2-AAF to background levels. Taken together, these data indicate that CHO cells metabolized N-acetoxy-2-AAF to a reactive derivative by N-deacetylation to N-acetoxy-2-AF, while N-hydroxy-2-AF reacted directly with DNA. The major pathway of N-hydroxy-2-AAF activation appeared to be an initial O-acetylation to N-acetoxy-2-AAF and this occurred to only a limited extent in the CHO cells. The initial step in the activation of 2-AAF and 2-AF was an N-oxidation to N-hydroxy-2-AAF and N-hydroxy-2-AF, respectively. The limited O-acetylase activity in CHO cells appeared to contribute to the low sensitivity of these cells toward mutation induction by arylamines and arylamides.
- Research Organization:
- National Center for Toxicological Research, Jefferson, AR (USA)
- OSTI ID:
- 7138346
- Journal Information:
- Environ. Mol. Mutagen.; (United States), Journal Name: Environ. Mol. Mutagen.; (United States) Vol. 11:2; ISSN ENMUE
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ACETYLAMINOFLUORENES
ADDUCTS
ANIMAL CELLS
AROMATICS
AZAARENES
BENZOPYRENE
CHO CELLS
CONDENSED AROMATICS
DNA ADDUCTS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROCARBONS
HYDROXY COMPOUNDS
HYPOXANTHINE
LABELLED COMPOUNDS
METABOLISM
MUTAGEN SCREENING
MUTAGENESIS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PURINES
SCREENING
TRANSFERASES
TRITIUM COMPOUNDS