2 acetylaminofluorene

Summary

Summary: A hepatic carcinogen whose mechanism of activation involves N-hydroxylation to the aryl hydroxamic acid followed by enzymatic sulfonation to sulfoxyfluorenylacetamide. It is used to study the carcinogenicity and mutagenicity of aromatic amines.

Top Publications

  1. Yovchev M, Grozdanov P, Zhou H, Racherla H, Guha C, Dabeva M. Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology. 2008;47:636-47 pubmed
    ..It is shown that Thy-1(+) cells are mesenchymal cells with characteristics of myofibroblasts/activated stellate cells. Transplantation experiments reveal that EpCAM(+) cells are true progenitors capable of repopulating injured rat liver...
  2. Suzuki N, Ohashi E, Hayashi K, Ohmori H, Grollman A, Shibutani S. Translesional synthesis past acetylaminofluorene-derived DNA adducts catalyzed by human DNA polymerase kappa and Escherichia coli DNA polymerase IV. Biochemistry. 2001;40:15176-83 pubmed
    ..et al. (2001) Biochemistry 40, 3717-3722], supporting a model in which pol kappa plays a role in translesion synthesis past acetylaminofluorene-derived lesions in mammalian cells...
  3. Paku S, Schnur J, Nagy P, Thorgeirsson S. Origin and structural evolution of the early proliferating oval cells in rat liver. Am J Pathol. 2001;158:1313-23 pubmed
  4. Yovchev M, Grozdanov P, Joseph B, Gupta S, Dabeva M. Novel hepatic progenitor cell surface markers in the adult rat liver. Hepatology. 2007;45:139-49 pubmed
    ..Moreover, study of progenitor cells purified with Ep-CAM antibodies from D-galactosamine injured rat liver, a noncarcinogenic model of progenitor cell activation, verified that progenitor cells expressed these markers...
  5. Gillet L, Alzeer J, SCHARER O. Site-specific incorporation of N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-AAF) into oligonucleotides using modified 'ultra-mild' DNA synthesis. Nucleic Acids Res. 2005;33:1961-9 pubmed
    ..Our synthetic approach should facilitate comprehensive studies of the mechanisms of repair and mutagenesis induced by dG-AAF adducts in DNA and should be of general use for the incorporation of base-labile functionalities into DNA...
  6. Pi L, Oh S, Shupe T, Petersen B. Role of connective tissue growth factor in oval cell response during liver regeneration after 2-AAF/PHx in rats. Gastroenterology. 2005;128:2077-88 pubmed
    ..To understand the molecular mechanism underlying this process, we investigated the role of connective tissue growth factor (CTGF), one of the candidate genes differentially expressed in Thy-1+ oval cells, in this liver injury model...
  7. Shibutani S, Suzuki N, Grollman A. Mutagenic specificity of (acetylamino)fluorene-derived DNA adducts in mammalian cells. Biochemistry. 1998;37:12034-41 pubmed
    ..dG-AAF was 3.8 times more mutagenic than dG-AF (11% vs 2.9%) in COS cells. We conclude from this study that dG-AAF and dG-AF produce G --> T transversions and, to a much lesser degree, G --> A transitions in mammalian cells...
  8. Petersen B, Bowen W, Patrene K, Mars W, Sullivan A, Murase N, et al. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284:1168-70 pubmed
    ..From these cells, a proportion of the regenerated hepatic cells were shown to be donor-derived. Thus, a stem cell associated with the bone marrow has epithelial cell lineage capability...
  9. Tan X, Suzuki N, Grollman A, Shibutani S. Mutagenic events in Escherichia coli and mammalian cells generated in response to acetylaminofluorene-derived DNA adducts positioned in the Nar I restriction enzyme site. Biochemistry. 2002;41:14255-62 pubmed
    ..3-21%, the higher value at G(2). We conclude from this study that the mutation potential of dG-AAF and dG-AF depends on the structure of the adduct, the sequence context of the lesion, and the host cell used for the experiment...

More Information

Publications62

  1. Guo D, Xie Z, Shen H, Zhao B, Wang Z. Translesion synthesis of acetylaminofluorene-dG adducts by DNA polymerase zeta is stimulated by yeast Rev1 protein. Nucleic Acids Res. 2004;32:1122-30 pubmed
    ..Consistent with the in vitro results, both Polzeta and Rev1 were found to be equally important for error-prone translesion synthesis across from AAF-dG DNA adducts in yeast cells...
  2. Dutta S, Li Y, Johnson D, Dzantiev L, Richardson C, Romano L, et al. Crystal structures of 2-acetylaminofluorene and 2-aminofluorene in complex with T7 DNA polymerase reveal mechanisms of mutagenesis. Proc Natl Acad Sci U S A. 2004;101:16186-91 pubmed
    ..In contrast, the dG-AF base at the templating position is not well defined by the electron density, consistent with weak binding to the polymerase and a possible interchange of this adduct between the syn and anti conformations...
  3. Shibutani S, Suzuki N, Grollman A. Mechanism of frameshift (deletion) generated by acetylaminofluorene-derived DNA adducts in vitro. Biochemistry. 2004;43:15929-35 pubmed
    ..Taken together, these results support the molecular mechanism for frameshift deletion proposed earlier by Shibutani and Grollman in which direct base insertion precedes misalignment [(1993) J. Biol. Chem. 268, 11703]...
  4. Gill J, Romano L. Mechanism for N-acetyl-2-aminofluorene-induced frameshift mutagenesis by Escherichia coli DNA polymerase I (Klenow fragment). Biochemistry. 2005;44:15387-95 pubmed
  5. Gupta P, Pandrangi R, Lee M, King C. Induction of mutations by N-acetoxy-N-acetyl-2-aminofluorene modified M13 viral DNA. Carcinogenesis. 1991;12:819-24 pubmed
    ..Molecular mechanisms for the induction of these mutations by DNA perturbations produced by the G-8-AAF adducts are discussed...
  6. Oh S, Witek R, Bae S, Zheng D, Jung Y, Piscaglia A, et al. Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Gastroenterology. 2007;132:1077-87 pubmed
    ..The present study analyzed whether the bone marrow cells are a source of hepatic oval cells involved in rat liver regeneration induced by 2-acetylaminofluorene (2-AAF) and 70% partial hepatectomy (PHx)...
  7. Gunz D, Hess M, Naegeli H. Recognition of DNA adducts by human nucleotide excision repair. Evidence for a thermodynamic probing mechanism. J Biol Chem. 1996;271:25089-98 pubmed
    ..Thus, an early step of DNA damage recognition involves thermodynamic probing of the duplex...
  8. Best D, Coleman W. Treatment with 2-AAF blocks the small hepatocyte-like progenitor cell response in retrorsine-exposed rats. J Hepatol. 2007;46:1055-63 pubmed
  9. Menthena A, Deb N, Oertel M, Grozdanov P, Sandhu J, Shah S, et al. Bone marrow progenitors are not the source of expanding oval cells in injured liver. Stem Cells. 2004;22:1049-61 pubmed
    ..These data demonstrate that the sources of oval cells and small hepatocytes in the injured liver are endogenous liver progenitors and that they do not arise through transdifferentiation from BM cells...
  10. Shibutani S, Suzuki N, Tan X, Johnson F, Grollman A. Influence of flanking sequence context on the mutagenicity of acetylaminofluorene-derived DNA adducts in mammalian cells. Biochemistry. 2001;40:3717-22 pubmed
    ..The mutational frequency and specificity of dG-AF vary significantly, depending on the nature of the bases flanking the lesion...
  11. Hansson J, Munn M, Rupp W, Kahn R, Wood R. Localization of DNA repair synthesis by human cell extracts to a short region at the site of a lesion. J Biol Chem. 1989;264:21788-92 pubmed
    ..DNA repair synthesis induced by the 2-(acetyl-amino)fluorene adduct took place in the damaged strand and was confined to a region within a 31-base pair restriction fragment around the adduct...
  12. Yasui M, Dong H, Bonala R, Suzuki N, Ohmori H, Hanaoka F, et al. Mutagenic properties of 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene, a persistent acetylaminofluorene-derived DNA adduct in mammalian cells. Biochemistry. 2004;43:15005-13 pubmed
  13. Furtado K, Pires P, Justulin L, Rodrigues M, Felisbino S, Barbisan L. Metalloproteinases 2 and 9 activity during promotion and progression stages of rat liver carcinogenesis. J Mol Histol. 2009;40:1-11 pubmed publisher
    ..Our findings suggest that MMP-2 may be associated with proliferative events induced by 2-AAF rather than with selective growth of PNL and that MMP-9 could be associated with progression of PNL and neoplastic mixed lesions...
  14. Smith C, Adkins D, Martin E, O Donovan M. Recommendations for design of the rat comet assay. Mutagenesis. 2008;23:233-40 pubmed publisher
    ..It is recommended that similar investigations of experimental variability should be performed to determine optimal experimental design in any laboratory using the rodent comet assay...
  15. Jenkins G, Parry J. Restriction site mutation (RSM) analysis of 2-acetylaminofluorene (2-AAF)-induced mouse liver mutations and comparison with the measurement of in vivo micronucleus induction in the bone marrows of (2-AAF)-treated mice. Teratog Carcinog Mutagen. 2000;20:107-17 pubmed
    ..Teratogenesis Carcinog. Mutagen. 20:107-117, 2000...
  16. Tsuda H, Asamoto M, Ogiso T, Inoue T, Ito N, Nagao M. Dose-dependent induction of liver and thyroid neoplastic lesions by short-term administration of 2-amino-3-methylimidazo[4,5-f]quinoline combined with partial hepatectomy followed by phenobarbital or low dose 3'-methyl-4-dimethylaminoazobenzene promo. Jpn J Cancer Res. 1988;79:691-7 pubmed
    ..The development of thyroid tumors initiated by the IQ treatment was significantly enhanced by the administration of PB, whereas Zymbal gland tumors induced by IQ did not show any correlation with either PB or 3'-Me-DAB treatment...
  17. Zhou C, Li Z, Diao H, Yu Y, Zhu W, Dai Y, et al. DNA damage evaluated by gammaH2AX foci formation by a selective group of chemical/physical stressors. Mutat Res. 2006;604:8-18 pubmed
  18. Guo D, Wu X, Rajpal D, Taylor J, Wang Z. Translesion synthesis by yeast DNA polymerase zeta from templates containing lesions of ultraviolet radiation and acetylaminofluorene. Nucleic Acids Res. 2001;29:2875-83 pubmed
    ..Secondly, more efficient bypass of these lesions may require nucleotide incorporation by other DNA polymerases followed by extension DNA synthesis by Polzeta...
  19. Makino Y, Yamamoto K, Tsuji T. Specific lectin bindings to oval cells and proliferated bile ductules. Gastroenterol Jpn. 1988;23:658-65 pubmed
  20. Hiramatsu N, Kishida T, Natake M. Effects of dose levels of autoxidized linoleic acid on the drug-metabolizing system in rat liver. J Nutr Sci Vitaminol (Tokyo). 1988;34:97-106 pubmed
    ..These results strongly supported the findings in a previous report wherein we observed the periodical effect of AL dose on the drug-metabolizing system...
  21. Sanchez A, Nagy P, Thorgeirsson S. STAT-3 activity in chemically-induced hepatocellular carcinoma. Eur J Cancer. 2003;39:2093-8 pubmed
    ..Therefore, the activity of the STAT-3 signal transduction pathway seems to be required for the growth of HCCs and could be a potential new target for therapeutic trials of this tumour type...
  22. Buterin T, Hess M, Gunz D, Geacintov N, Mullenders L, Naegeli H. Trapping of DNA nucleotide excision repair factors by nonrepairable carcinogen adducts. Cancer Res. 2002;62:4229-35 pubmed
    ..Thus, the efficiency of excision repair in response to bulky carcinogen-DNA damage is dependent on an antagonistic interaction with both substrate and decoy adducts...
  23. Williams J, Oh S, Jorgensen M, Steiger N, Darwiche H, Shupe T, et al. The role of the Wnt family of secreted proteins in rat oval "stem" cell-based liver regeneration: Wnt1 drives differentiation. Am J Pathol. 2010;176:2732-42 pubmed publisher
    ..Furthermore, changes in Wnt1 levels are required for the efficient regeneration of the liver by oval cells during massive hepatic injury...
  24. Leite A, Correa Giannella M, Dagli M, Fortes M, Vegas V, Giannella Neto D. Fibronectin and laminin induce expression of islet cell markers in hepatic oval cells in culture. Cell Tissue Res. 2007;327:529-37 pubmed
    ..Our results suggest that these ECM proteins can be used in protocols of OC transdifferentiation aimed at reducing the period necessary for complete transdifferentiation...
  25. Chinzei R, Tanaka Y, Shimizu Saito K, Hara Y, Kakinuma S, Watanabe M, et al. Embryoid-body cells derived from a mouse embryonic stem cell line show differentiation into functional hepatocytes. Hepatology. 2002;36:22-9 pubmed
    ..In conclusion, our in vitro and in vivo experiments revealed that cultured EBs contain functional hepatocytes or hepatocyte-like cells...
  26. Lim L, Corbett B, Corbett M. Irreversible inhibition of the cytosolic metabolism of N-hydroxy-2-acetylaminofluorene by its glycolyl analog. Cancer Lett. 1987;37:205-11 pubmed
    ..In contrast, both the glycolyl and acetyl hydroxamic acid derivatives were metabolized to a similar extent by enzymes in the microsomal fraction...
  27. Lindeman B, Skarpen E, Huitfeldt H. Stress protein expression in rat liver during tumour promotion: induction of heat-shock protein 27 in hepatocytes exposed to 2-acetylaminofluorene. Carcinogenesis. 1998;19:1559-63 pubmed
    ..Enzyme altered preneoplastic foci were not found to overexpress HSPs. Thus, HSP induction does not seem to be a general mechanism underlying the increased stress tolerance observed in such lesions...
  28. Shiota G, Kunisada T, Oyama K, Udagawa A, Nomi T, Tanaka K, et al. In vivo transfer of hepatocyte growth factor gene accelerates proliferation of hepatic oval cells in a 2-acetylaminofluorene/partial hepatectomy model in rats. FEBS Lett. 2000;470:325-30 pubmed
    ..Our results suggest that in vivo transfer of the HGF gene into liver accelerates proliferation of hepatic oval cells in the Solt-Farber model in rats...
  29. Carrasco Legleu C, Sánchez Pérez Y, Marquez Rosado L, Fattel Fazenda S, Arce Popoca E, Hernández García S, et al. A single dose of caffeic acid phenethyl ester prevents initiation in a medium-term rat hepatocarcinogenesis model. World J Gastroenterol. 2006;12:6779-85 pubmed
    ..To study of the effect of caffeic acid phenethyl ester (CAPE) on the initiation period in a medium-term assay of hepatocarcinogenesis...
  30. Kolanczyk R, Gutmann H, Rutks I. Effect of bovine serum albumin on the extent of ortho rearrangement of N-(sulfooxy)-2-fluorenylacetamide and of enzymatically activated N-hydroxy-2-fluorenylacetamide and on the binding of reactive esters to nucleic acids. Chem Res Toxicol. 1992;5:274-9 pubmed
    ..The data support the view that the reactive electrophile is N-acetoxy-2-fluorenamine, resulting from the N,O-transacetylation of N-hydroxy-2-fluorenylacetamide.(ABSTRACT TRUNCATED AT 250 WORDS)..
  31. Inami K, Okazawa M, Mochizuki M. Mutagenicity of aromatic amines and amides with chemical models for cytochrome P450 in Ames assay. Toxicol In Vitro. 2009;23:986-91 pubmed publisher
    ..Furthermore, we concluded that the AAF mutagenicity in the presence of 4-MPy/t-BuOOH is derived from N-hydroxylacetylamino compounds...
  32. Kiyosawa N, Ando Y, Watanabe K, Niino N, Manabe S, Yamoto T. Scoring multiple toxicological endpoints using a toxicogenomic database. Toxicol Lett. 2009;188:91-7 pubmed publisher
    ..The D-score will be useful for high-throughput toxicity screening using a toxicogenomic database and biomarkers...
  33. Wierckx F, Wedzinga R, Timmers Reker A, Beland F, Meerman J, Mulder G. DNA adduct formation in liver following the administration of [3H]2-nitrofluorene to rats in vivo. Carcinogenesis. 1991;12:2053-8 pubmed
    ..In vitro experiments with inhibitors of the enzyme epoxide hydrolase indicated that epoxidation of 2-NF may play a role in the microsomal bioactivation of this compound...
  34. Williams G, Iatropoulos M, Jeffrey A. Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine. Toxicol Pathol. 2000;28:388-95 pubmed
    ..The finding of no-effect levels provides a basis for understanding why low-level environmental exposures of humans to even DNA-reactive carcinogens may convey no cancer risk...
  35. Perrone C, Ahr H, Duan J, Jeffrey A, Schmidt U, Williams G, et al. Embryonic turkey liver: activities of biotransformation enzymes and activation of DNA-reactive carcinogens. Arch Toxicol. 2004;78:589-98 pubmed
    ..Thus, turkey embryos could be utilized to investigate potential chemical toxicity and carcinogenicity...
  36. Ahmed S, Rahman A, Mathur M, Athar M, Sultana S. Anti-tumor promoting activity of Asteracantha longifolia against experimental hepatocarcinogenesis in rats. Food Chem Toxicol. 2001;39:19-28 pubmed
    ..longifolia seeds against chemically-induced hepatocarcinogenesis in Wistar rats...
  37. Burnouf D, Fuchs R. The early detection of frameshift mutations induced by a food-borne carcinogen in rats: a new tool for molecular epidemiology. Mutat Res. 2000;462:281-91 pubmed
    ..This assay is sensitive enough to allow early detection of induced mutations and therefore allows to differentiate between unexposed animal and those exposed for a period as short as 1 week...
  38. Pogribny I, Muskhelishvili L, Tryndyak V, Beland F. The tumor-promoting activity of 2-acetylaminofluorene is associated with disruption of the p53 signaling pathway and the balance between apoptosis and cell proliferation. Toxicol Appl Pharmacol. 2009;235:305-11 pubmed publisher
  39. Lin H, Mao Q, Wang Y, Jiang L. Proliferation of L02 human hepatocytes in tolerized genetically immunocompetent rats. World J Gastroenterol. 2008;14:2329-37 pubmed
    ..To investigate whether human hepatocytes could proliferate after transplantation to normal immunocompetent rats treated with 2-acetaminofluorene or retrorsine and partial hepatectomy...
  40. Carothers A, Steigerwalt R, Urlaub G, Chasin L, Grunberger D. DNA base changes and RNA levels in N-acetoxy-2-acetylaminofluorene-induced dihydrofolate reductase mutants of Chinese hamster ovary cells. J Mol Biol. 1989;208:417-28 pubmed
    ..Taken together with the results of other mutagens at this locus, we conclude that the low dhfr mRNA phenotype is correlated with the presence of nonsense codons in exons II to V but not in the last exon of the dhfr gene...
  41. Harris C, Stark K, Juchau M. Glutathione status and the incidence of neural tube defects elicited by direct acting teratogens in vitro. Teratology. 1988;37:577-90 pubmed
  42. Vian L, Yusuf A, Guyomard C, Cano J. The Liverbeads as a tool for the comet assay. Mutat Res. 2002;519:163-70 pubmed
    ..Due to the maintenance of specific functions assessed by the observed capacity to metabolize xenobiotics, Liverbeads represent a suitable tool system, easy to handle, for the detection of promutagens using the comet assay...
  43. Ohlson L, Koroxenidou L, Porsch Hällström I. Mitoinhibitory effects of the tumor promoter 2-acetylaminofluorene in rat liver: loss of E2F-1 and E2F-3 expression and cdk 2 kinase activity in late G1. J Hepatol. 2004;40:957-62 pubmed
    ..Examine the mitoinhibitory effect of the liver tumor promoter 2-acetylaminofluorene (2-AAF) in vivo, with focus on the proteins regulating G1- and S progression...
  44. Chang C, Hsieh Y, Chung J, Tsai H, Tsai C. Leukemia inhibitory factor decreases the arylamine N-acetyltransferase activity in human cumulus granulosa cells. J Assist Reprod Genet. 2001;18:660-4 pubmed
    ..To evaluate the activities of acetyl coenzyme A (AcCoA):arylamine N-acetyltransferase (NAT) of intact cumulus granulosa cells and the role of leukemia inhibitory factor (LIF) upon their NAT activities...
  45. Malejka Giganti D, Magat W, Adelmann A, Decker R. Metabolite profile in milk of lactating rats after treatment with a carcinogen, N-2-fluorenylacetamide. Drug Metab Dispos. 1987;15:760-6 pubmed
    ..Since 2-NOF has been reported to form adducts with unsaturated lipids, the effect of treatment of lactating rats with 2-FAA on the fatty acid composition of milk lipids was examined.(ABSTRACT TRUNCATED AT 250 WORDS)..
  46. Waddell W. Critique of dose response in carcinogenesis. Hum Exp Toxicol. 2006;25:413-36 pubmed
    ..Experiments showing that cumulative dose is a better metric than daily dose may require reevaluating almost all carcinogenicity studies...
  47. Li H, Lee G, Liu J, Nomura K, Ohtake K, Kitagawa T. Low frequency of ras activation in 2-acetylaminofluorene- and 3'-methyl-4-(dimethylamino)azobenzene-induced rat hepatocellular carcinomas. Cancer Lett. 1991;56:17-24 pubmed
  48. Cho B, Zhou L. Probing the conformational heterogeneity of the acetylaminofluorene-modified 2'-deoxyguanosine and DNA by 19F NMR spectroscopy. Biochemistry. 1999;38:7572-83 pubmed
    ..et al. (1997) J. Am. Chem. Soc. 119, 5384-5389]. The exclusive stacked nature of the AAF adducts may provide insight into why AAF adducts are more mutagenic and prone to repair than the nonacetylated AF adducts...
  49. Paku S, Nagy P, Kopper L, Thorgeirsson S. 2-acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: confocal and electron microscopic studies. Hepatology. 2004;39:1353-61 pubmed
    ..In conclusion, these results indicate the rate of oval cell differentiation into hepatocytes is context dependent and suggest that, under favorable conditions, oval cells can complete this process much faster than previously appreciated...
  50. Lake B, Edwards A, Price R, Phillips B, Renwick A, Beamand J, et al. Lack of effect of furfural on unscheduled DNA synthesis in the in vivo rat and mouse hepatocyte DNA repair assays and in precision-cut human liver slices. Food Chem Toxicol. 2001;39:999-1011 pubmed
    ..Moreover, human liver slice studies suggest that furfural is also not a genotoxic agent in human liver...
  51. Silveira E, Naves M, Vannucchi H, Jordão Junior A, Dagli M, Moreno F. Vitamin A and all-trans and 9-cis retinoic acids inhibit cell proliferation during the progression phase of hepatocarcinogenesis in Wistar rats. Nutr Cancer. 2001;39:244-51 pubmed
    ..Therefore, the anticarcinogenic effects that have been attributed to these retinoids could be partially related to their capacity of inhibiting in vivo cell proliferation...
  52. Zhang Z, Sun J, Sun L. Statistical analysis of current status data with informative observation times. Stat Med. 2005;24:1399-407 pubmed
    ..The procedures can be easily implemented and are applied to two motivating examples...
  53. Asamoto M, Shichino Y, Tsuda H, Ito N. Inhibition of rat hepatic glutathione S-transferase placental form positive foci development by concomitant administration of antioxidants to carcinogen-treated rats. Cancer Lett. 1990;55:25-9 pubmed