2-Aminofluorene carcinogen

The metabolic formation of N-sulfonyloxy-N-acetyl-2-aminofluorene (N-sulfonyloxy-AAF) and its observed electrophilic reactivity, provided the first evidence for the importance of enzymatic conjugation reactions in chemical carcinogenesis (23,24). This reaction was shown to be catalyzed by PAPS-dependent sulfotrans-ferases that are located predominantly in liver cytosol and has been subsequently demonstrated for N-hydroxy arylamide metabolites of several other carcinogens, including N-acetyl-4-aminobiphenyl (AABP), benzidine, N-acetyl-2-aminophenanthrene and phenacetin. 

Lai CC, Miller JA, Miller EC, et al. N-sulfooxy-2-aminofluorene is the major ultimate electrophilic and carcinogenic metabolite of N-hydroxy-2-acetylaminofluorene in the livers of infant male C57BL/6J x C3H/HeJ FI (B6C3F1) mice. Carcinogenesis 1985 6(7) 1037— 1045. 

Prostaglandin synthetase, peroxidase or lipid peroxidation have been shown to oxidise arylamine xenobiotics to reactive species that bind extensively to DNA. The binding could be an initial event in the toxic or carcinogenic process. Evidence is presented that cation radicals are involved in the formation of the various oxidation products and DNA adduct formation with the carcinogen aminofluorene. Furthermore methylaminoazobenzene (butter yellow) was found to form the same major GSH adduct as is formed in vivo. 

Translesion synthesis with DNA Pol of the A-acetyl-2-aminofluorene adduct of guanosine (88) is inefficient with templates containing (88). In the presence of the Revl protein, translesion synthesis occurs and dCTP is the major nucleotide incorporated opposite it, and studies with a mutant DNA Pol I gave similar results. Benzo[a]pyrene is a potent environmental carcinogen, which when metabolised leads to u t -benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide anti-BPDE). With dG, the major lesion is (+)-tra w-a h-B[a]P-A -dG, (89), and is usually repaired by the nucleotide excision repair (NER) pathway. The translesion synthesis past (89) has been examined with a number of polymerases. With human RNA Pol II, (89) is a block to synthesis, whilst DNA Pol k preferentially incorporated the correct nucleotide. In yeast cells, Pol induced a large number of mutations involving Pol p, whilst Pol p alone contributed to 1-3 deletions or insertions. The NER of (89) with UvrB proteins was also studied. ... 

N-hydroxylation of aromatic amides, which occurs to a minor extent, is of some toxicological intcre.st. since this biotrunsfomiation pathway miiy lead to the formation of chemically reactive intermediates. Several examples of cytotoxicity or carcinogenicity associated with metabolic N-hydroxylation of the parent aromatic amide have been reported. For example, the well-known hepatocareiniigcnic 2-acctyl-aminofluorene (AAF) undergoes an N-hydmxylation reaction catalyzed by cytochrome P-450 to form the cnrre.sp(ind-ing N-hydroxy metabolite (also called a hydroxamic... 

Acetylaminofluorene is not carcinogenic 2-acetylaminofluorene is carcinogenic. 2-Acetylami-nofluorene can be metabolized to form N-hydroxy-acetylaminofluorene and 2-aminofluorene, which may covalently bind to the DNA and macromolecules. Ring hydroxylation, however, leads to the formation and excretion of water-soluble conjugates (e.g., glucuronides) of the respective hydroxylated metabolites and detoxification. 

As per OSHA, workers exposure to 2-acetyl-aminofluorene is to be controlled through the required use of engineering controls, work practices, and personal protective equipment, including respirators. Identified as an occupational carcinogen without establishing a permissible exposure limit. NIOSH considers 2-acetylaminofluorene to be a potential occupational carcinogen. NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. 

Marshall MV, Arnott MS, Jacobs MM, et al. 1979. Selenium effects on the carcinogenicity and metabolism of 2-acetyl aminofluorene. Cancer Letters 7 331-338. 

Figure 10.5 (a) Template/primer sequence contexts used for dynamic l9F-NMR and DSC experiments [79]. (b) Example n + 3 translesion synthesis models of BF complexed with AF-modified template/primer DNA n + 3 dC-match (B-type conformer) and n + 3 dA-mismatch (W-conformer) [56]. The carcinogenic aminofluorene moiety is... 

Cho, B.P., Beland, F.A., and Marques, M.M. (1994) NMR structural studies of a 15-mer DNA duplex from a ras protooncogene modified with the carcinogen 2-aminofluorene conformational heterogeneity. Biochemistry, 33, 1373-1384. 

There are two issues with P450 4B1. First, the enzyme has been shown to activate carcinogens, for example, 2-aminofluorene, and could be a risk factor in bladder cancer . The level of P450 4B1 in tumorous tissue was not higher than in the surrounding tissue, levels of bladder P450 4B1 were higher in tumor patients than in controls . 

White, G. L. and R. H. Heflich. 1985. Mutagenic activation of 2-aminofluorene by fluorescent light. Teratogen. Carcinogen. Mutagen. 5, 63-73. 

Frederick CB, Mays JB, Ziegler DM, Guengerich FP, Kadlubar FF. Cytochrome P450 and flavin-containing monooxygenase-catalyzed formation of the carcinogen N-hydroxy-2-aminofluorene, and its covalent binding to nuclear DNA. Cancer Res 1982 42 2671-2677. 

Bichara, M., and Fuchs, R. P. P. (1985). Binding and mutation spectra of the carcinogen N-2-aminofluorene. A correladon between the conformation of the premuta-genic lesion and the mutation specificity. / Mol. BioL 183, 341-351. 

Floyd. R. A., Soong. L. M., and Culver, P. L. Horseradish peroxidase/ hydrogen peroxide-catalyzed oxidation of the carcinogen M-hydroxy-Af-acetyl-2-aminofluorene as affected by cyanide and ascorbate. Cancer Res.. 36 1510-1519.1976. 

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