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Chemical Compound Review:

CHEMBL314422 N-(9H-fluoren-2- yl)hydroxylamine

Synonyms: CCRIS 1067, AG-J-36237, HSDB 2113, AC1Q7DJS, LS-77424, ...

Beland, F.A. et al., Gupta, P.K. et al., Hein, D.W. et al., Granger-Schnarr, M., Lutgerink, J.T. et al., et al.

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Disease relevance of N-Hydroxy-aminofluorene

The mutagenicity of N-hydroxy-2-acetylaminofluorene and N-hydroxyphenacetin and their respective deacetylated metabolites, N-hydroxy-2-aminofluorene and 2-nitrosofluorene, and N-hydroxyphenetidine and rho-nitrosophenetole was determined in nitroreductase deficient Salmonella tester strains TA 98FR and TA100FR [1].
To examine the effects of aminofluorene-DNA adduct formation on the biological activity of DNA, single-stranded (ss) phi X174 DNA and phi X174 replicative form (RF) DNA were modified to different extents with 3H-labeled N-hydroxy-2-aminofluorene and subsequently transfected to Escherichia coli spheroplasts with different repair capabilities [2].
The specificity of mutagenesis in single-stranded and its complementary double-stranded DNA of the bacteriophage M13mp8 induced by N-hydroxy-2-aminofluorene (N-OH-AF) was analyzed after transfection into its bacterial host Escherichia coli, strain JM103 [3].
The differential effect of benzamide upon the toxicity and mutations produced in Chinese hamster ovary cells by N-methyl nitrosourea, N-ethyl nitrosourea and N-hydroxy-2-aminofluorene [4].

High impact information on N-Hydroxy-aminofluorene

N-Hydroxy-2-aminofluorene (CAS: 53-94-1; N-OH-AF), N-hydroxy-2-acetylaminofluorene (CAS: 53-95-2; N-OH-AAF), and the N-glucuronide of N-OH-AF induced UDS in HCV 29, HU 1734, and HU 1752 [5].
Metabolic activation of N-hydroxy-2-aminofluorene catalyzed by both NAT1 and NAT2 was resistant to 100 microM paraoxon, an inhibitor of microsomal deacetylases [6].
Acetyl coenzyme A dependent activation of 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-OH-Glu-P-1) and 3-hydroxyamino-1-methyl-5H-pyrido [4,3-b]indole (N-OH-Trp-P-2) was investigated using cytosols from hepatic and extrahepatic tissues of various animal species in comparison with that of N-hydroxy-2-aminofluorene [7].
Cytochrome P-450- and flavin-containing monooxygenase-catalyzed formation of the carcinogen N-hydroxy-2-aminofluorene and its covalent binding to nuclear DNA [8].
Metabolism of N-hydroxy-2-acetylaminofluorene and N-hydroxy-2-aminofluorene by guinea pig liver microsomes [9].

Biological context of N-Hydroxy-aminofluorene

The substrate specificity of these enzymes in rat, guinea pig, monkey, baboon, pig, and human liver has been examined by measuring the AT-mediated nucleic acid binding of the N-formyl, N-acetyl, and N-propionyl derivatives of N-hydroxy-2-aminofluorene [10].
Comparison of mutagenesis induced in single- and double-stranded M13 viral DNA by treatment with N-hydroxy-2-aminofluorene [3].
The S-acetyl coenzyme A-dependent metabolic activation of the carcinogen N-hydroxy-2-aminofluorene by human liver cytosol and its relationship to the aromatic amine N-acetyltransferase phenotype [11].
Using a forward mutational assay and recA441 lexA (Def) host bacteria, we show that the result can be extended not only to other mutagens promoting base pair substitution mutations (Apurinic sites, Ap sites and N-hydroxy-N-2-aminofluorene, N-OH-AF) but also mutagens promoting frameshift mutations (N-Acetoxy-N-2-acetylaminofluorene, N-AcO-AAF) [12].
IC50 values of PCP for the activation of 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-OH-Glu-P-1), 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-OH-Trp-P-2) and N-hydroxy-2-aminofluorene (N-OH-AF) were 20, 25 and 17 microM, respectively, in hamster cytosol system [13].

Anatomical context of N-Hydroxy-aminofluorene

Rat, dog, human, and pig liver microsomes catalyzed the formation of N-hydroxy-2-aminofluorene (N-OH-AF) from AF at rates of 1.6, 1.0, 1.2, and 3.5 nmol/min/mg protein, respectively [8].
This product had a high-pressure liquid chromatography retention time and pH-dependent partition characteristics identical to those of an adduct synthesized by an acid-dependent (pH 4.6) reaction of N-hydroxy-2-aminofluorene with calf thymus DNA [10].
N-Deacylations of N-OH-2-FBA and N-OH-2-FAA to N-2-fluorenylhydroxylamine (N-OH-2-FA) were faster by liver than serosa and by microsomes than cytosols [14].
Purified red blood cell cytosol is able to activate 2-aminofluorene (2AF) to N-hydroxy-2-aminofluorene [15].
Hepatocytes were exposed in vitro to the hepatocarcinogen N-hydroxy-2-aminofluorene (N-OH-AAF) in order to determine the nature and repair of DNA adducts formed [16].

Associations of N-Hydroxy-aminofluorene with other chemical compounds

In rapid acetylator hamster colon, NAT2/NAT1 activity ratios were 18 and 13 for the N-acetylation of 2-aminofluorene and 4-aminobiphenyl and 28 for the O-acetylation of N-hydroxy-2-aminofluorene [6].
A mutational hot spot induced by N-hydroxy-aminofluorene in dihydrofolate reductase mutants of Chinese hamster ovary cells [17].
Thus, the mechanism of inactivation of NAT1 by N-OH-AAF involves NAT1-catalyzed deacetylation to afford N-hydroxy-2-aminofluorene, which after oxidative conversion to 2-nitrosofluorene, forms a sulfinamide adduct by reacting with Cys68 [18].
The corresponding hydroxylamine, N-hydroxy-2-aminofluorene (N-OH-AF), reduced cytochrome b specifically through center N of the cytochrome bc1 complex [19].
Both the NAT2(191) and NAT2(341/803) mutant alleles expressed functional N-acetyltransferases capable of catalyzing both arylamine N-acetylation and the metabolic activation (via O-acetylation) of N-hydroxy-2-aminofluorene [20].

Gene context of N-Hydroxy-aminofluorene

On an adduct basis N-Acetoxy-N-2-acetylaminofluorene was shown to induce the protein RecA at a similar level as U.V. On the other hand, N-hydroxy-N-2-aminofluorene shows only a poor induction capacity of the RecA protein [21].
Recognition of damage induced by N-hydroxy-2-aminofluorene (N-OH-AF) and N-acetoxy-2-(acetylamino)fluorene (NAAAF) in both phi X174 RFI supercoiled DNA and a linear DNA fragment by purified UVRA, UVRB, and UVRC proteins was investigated [22].
In contrast, no AST IV catalyzed sulfation of N-hydroxy-2-aminofluorene was detected under conditions that prevented the oxidation of N-hydroxy-2-aminofluorene [23].
Mutagenicity of 4 N- and O-acyl derivatives of N-hydroxy-2-aminofluorene (acyl: acetyl or myristoyl residue) was examined in V79 Chinese hamster cells in the absence of a metabolic activation system [24].

Analytical, diagnostic and therapeutic context of N-Hydroxy-aminofluorene

Extracts of human red blood cell cytosol incubated with 2AF were analyzed by gas chromatography: N-hydroxy-2-aminofluorene was identified as a metabolite [25].

References

Mutagenicity of N-hydroxy-2-acetylaminofluorene and N-hydroxy-phenacetin and their respective deacetylated metabolites in nitroreductase deficient Salmonella TA98FR and TA100FR. Wirth, P.J., Alewood, P., Calder, I., Thorgeirsson, S.S. Carcinogenesis (1982) [Pubmed]
By-pass of the major aminofluorene-DNA adduct during in vivo replication of single- and double-stranded phi X174 DNA treated with N-hydroxy-2-aminofluorene. Lutgerink, J.T., Retèl, J., Westra, J.G., Welling, M.C., Loman, H., Kriek, E. Carcinogenesis (1985) [Pubmed]
Comparison of mutagenesis induced in single- and double-stranded M13 viral DNA by treatment with N-hydroxy-2-aminofluorene. Gupta, P.K., Lee, M.S., King, C.M. Carcinogenesis (1988) [Pubmed]
The differential effect of benzamide upon the toxicity and mutations produced in Chinese hamster ovary cells by N-methyl nitrosourea, N-ethyl nitrosourea and N-hydroxy-2-aminofluorene. Heflich, R.H., Morris, S.M., White, G.L., Beland, F.A. Mutat. Res. (1985) [Pubmed]
Induction of DNA repair synthesis in human urothelial cells by the N-hydroxy metabolites of carcinogenic arylamines. Wang, C.Y., Christensen, B., Zukowski, K., Morton, K.C., Lee, M.S. J. Natl. Cancer Inst. (1984) [Pubmed]
Metabolic activation of N-hydroxy-2-aminofluorene and N-hydroxy-2-acetylaminofluorene by monomorphic N-acetyltransferase (NAT1) and polymorphic N-acetyltransferase (NAT2) in colon cytosols of Syrian hamsters congenic at the NAT2 locus. Hein, D.W., Doll, M.A., Gray, K., Rustan, T.D., Ferguson, R.J. Cancer Res. (1993) [Pubmed]
Acetyl coenzyme A dependent activation of N-hydroxy derivatives of carcinogenic arylamines: mechanism of activation, species difference, tissue distribution, and acetyl donor specificity. Shinohara, A., Saito, K., Yamazoe, Y., Kamataki, T., Kato, R. Cancer Res. (1986) [Pubmed]
Cytochrome P-450- and flavin-containing monooxygenase-catalyzed formation of the carcinogen N-hydroxy-2-aminofluorene and its covalent binding to nuclear DNA. Frederick, C.B., Mays, J.B., Ziegler, D.M., Guengerich, F.P., Kadlubar, F.F. Cancer Res. (1982) [Pubmed]
Metabolism of N-hydroxy-2-acetylaminofluorene and N-hydroxy-2-aminofluorene by guinea pig liver microsomes. Razzouk, C., Batardy-Grégoire, M., Roberfroid, M. Cancer Res. (1982) [Pubmed]
Acyltransferase-mediated binding of N-hydroxyarylamides to nucleic acids. Beland, F.A., Allaben, W.T., Evans, F.E. Cancer Res. (1980) [Pubmed]
The S-acetyl coenzyme A-dependent metabolic activation of the carcinogen N-hydroxy-2-aminofluorene by human liver cytosol and its relationship to the aromatic amine N-acetyltransferase phenotype. Flammang, T.J., Yamazoe, Y., Guengerich, F.P., Kadlubar, F.F. Carcinogenesis (1987) [Pubmed]
Base pair substitution and frameshift mutagenesis induced by apurinic sites and two fluorene derivatives in a recA441 lexA (Def) strain. Granger-Schnarr, M. Mol. Gen. Genet. (1986) [Pubmed]
Inhibition of acetyl-coenzyme A dependent activation of N-hydroxyarylamines by phenolic compounds, pentachlorophenol and 1-nitro-2-naphthol. Shinohara, A., Saito, K., Yamazoe, Y., Kamataki, T., Kato, R. Chem. Biol. Interact. (1986) [Pubmed]
Activation of the carcinogens N-hydroxy-N-2-fluorenylbenzamide and N-hydroxy-N-2-fluorenylacetamide via deacylations and acetyl transfers by rat peritoneal serosa and liver. Ritter, C.L., Malejka-Giganti, D. Carcinogenesis (1994) [Pubmed]
Oxidative activation of 2-aminofluorene by human red blood cell cytosol. Duverger-van Bogaert, M., Wiame, D., Stecca, C. Biochem. Pharmacol. (1992) [Pubmed]
Metabolic activation in isolated rat hepatocytes. Casciano, D.A. SAAS Bull. Biochem. Biotechnol. (1990) [Pubmed]
A mutational hot spot induced by N-hydroxy-aminofluorene in dihydrofolate reductase mutants of Chinese hamster ovary cells. Carothers, A.M., Urlaub, G., Mucha, J., Yuan, W., Chasin, L.A., Grunberger, D. Carcinogenesis (1993) [Pubmed]
Mass spectrometric investigation of the mechanism of inactivation of hamster arylamine N-acetyltransferase 1 by N-hydroxy-2-acetylaminofluorene. Guo, Z., Wagner, C.R., Hanna, P.E. Chem. Res. Toxicol. (2004) [Pubmed]
2-Nitrosofluorene and N-hydroxy-2-aminofluorene react with the ubiquinone-reduction center (center N) of the mitochondrial cytochrome bc1 complex. Klöhn, P.C., Brandt, U., Neumann, H.G. FEBS Lett. (1996) [Pubmed]
Cloning, expression, and functional characterization of two mutant (NAT2(191) and NAT2(341/803)) and wild-type human polymorphic N-acetyltransferase (NAT2) alleles. Ferguson, R.J., Doll, M.A., Rustan, T.D., Gray, K., Hein, D.W. Drug Metab. Dispos. (1994) [Pubmed]
Different levels of induction of RecA protein in E. coli (PQ 10) after treatment with two related carcinogens. Salles, B., Lang, M.C., Freund, A.M., Paoletti, C., Daune, M., Fuchs, R.P. Nucleic Acids Res. (1983) [Pubmed]
Recognition and repair of 2-aminofluorene- and 2-(acetylamino)fluorene-DNA adducts by UVRABC nuclease. Pierce, J.R., Case, R., Tang, M.S. Biochemistry (1989) [Pubmed]
Oxidation-dependent inactivation of aryl sulfotransferase IV by primary N-hydroxy arylamines during in vitro assays. King, R.S., Duffel, M.W. Carcinogenesis (1997) [Pubmed]
Mutagenicity of some N- and O-acyl derivatives of N-hydroxy-2-aminofluorene in V79 Chinese hamster cells. Kuroki, T., Bartsch, H. Cancer Lett. (1979) [Pubmed]
Activation of some aromatic amines to mutagenic products by human red blood cell cytosol. Duverger-van Bogaert, M., Crutzen-Fayt, M.C., Stecca, C. Mutat. Res. (1991) [Pubmed]

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