関: 2-AAF、2-acetylaminofluorene

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/12 21:11:27」(JST)

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2-Acetylaminofluorene (AAF,^[4] 2-AAF) is a carcinogenic and mutagenic derivative of fluorene. It is used as a biochemical tool in the study of carcinogenesis. It induces tumors in a number of species in the liver, bladder and kidney. The metabolism of this compound in the body by means of biotransformation reactions is the key to its carcinogenicity. 2-AAF is a substrate for cytochrome P-450 (CYP) enzyme, which is a part of a super family found in almost all organisms. This reaction results in the formation of N-hydroxy-2-acetylaminofluorene which is a proximal carcinogen and is more potent than the parent molecule. The N-hydroxy metabolite undergoes several enzymatic and non-enzymatic rearrangements. It can be O-acetylated by cytosolic N-acetyltransferase enzyme to yield N-acetyl-N-acetoxyaminofluorene. This intermediate can spontaneously rearrange to form the arylamidonium ion and a carbonium ion which can interact directly with DNA to produce DNA adducts. In addition to esterification by acetylation, the N-hydroxy derivative can be O-sulfated by cytosolic sulfur transferase enzyme giving rise to the N-acetyl-N-sulfoxy product.

In addition, the cytosolic N,O-aryl hydroxamic acid acyltransferase enzyme catalyzes the transfer of the acetyl group from the N atom of the N-OH-2-AAF to the O atom of the N-OH group to produce N-acetoxy-2-aminofluorene (N-OH-2-AF). This reactive metabolite spontaneously decomposes to form a nitrenium ion which will also react with DNA. However, the product of this latter reaction is the deacetylated aminofluorene adduct. The interconversion of amide and amine metabolites of 2-AAF can further occur via the microsomal enzyme deacetylase producing the N-hydroxy metabolite of the amine derivative. Subsequent esterification of the aryl hydroxylamine by sulfur transferase yields the sulfate ester which also spontaneously decompose to form nitrenium ion. The reactive nitrenium, carbonium and arylamidonium ion metabolites of 2-AAF react with the nucleophilic groups in DNA, proteins and endogenous thiols like glutathione. Other metabolites such as the N,O-glucuronide, although not directly activated products, can be important in the carcinogenic process because they are capable of degradation to proximal N-hydroxy metabolites. This metabolite is presumed to be involved in formation of bladder tumors. The mechanism for this is thought to involve degradation of glucuronide in the bladder due to acidic pH of urine.

References

^ ^a ^b "NIOSH Pocket Guide to Chemical Hazards". Centers for Disease Control and Prevnetion.
^ ^a ^b ^c "NIOSH Pocket Guide to Chemical Hazards #0007". National Institute for Occupational Safety and Health (NIOSH).
^ "2-Acetylaminofluorene - PubChem Public Chemical Database". The PubChem Project. USA: National Center for Biotechnology Information. Descriptors Computed from Structure.
^ Logan, Carolynn M.; Rice, M. Katherine (1987). Logan's Medical and Scientific Abbreviations. Philadelphia: J. B. Lippincott Company. p. 3. ISBN 0-397-54589-4.

English Journal

Discrimination of genotoxic and non-genotoxic hepatocarcinogens by statistical analysis based on gene expression profiling in the mouse liver as determined by quantitative real-time PCR.

Watanabe T, Suzuki T, Natsume M, Nakajima M, Narumi K, Hamada S, Sakuma T, Koeda A, Oshida K, Miyamoto Y, Maeda A, Hirayama M, Sanada H, Honda H, Ohyama W, Okada E, Fujiishi Y, Sutou S, Tadakuma A, Ishikawa Y, Kido M, Minamiguchi R, Hanahara I, Furihata C.SourceFunctional Genomics Laboratory, School of Science and Engineering, Aoyama Gakuin University, Fuchinobe 5-10-1, Chuo-ku, Sagamihara, Kanagawa 252-5258, Japan.
Mutation research.Mutat Res.2012 Sep 18;747(2):164-75. Epub 2012 May 23.
The general aim of the present study is to discriminate between mouse genotoxic and non-genotoxic hepatocarcinogens via selected gene expression patterns in the liver as analyzed by quantitative real-time PCR (qPCR) and statistical analysis. qPCR was conducted on liver samples from groups of 5 male,
PMID 22634710

Binary and ternary binding affinities between exonuclease-deficient Klenow fragment (K-exo-) and various arylamine DNA lesions characterized by surface plasmon resonance.

Vaidyanathan VG, Xu L, Cho BP.AbstractWe used surface plasmon resonance (SPR) to characterize the binding interactions between exonulease-free Klenow fragment (Kf-exo-) and unmodified and modified dG adducts derived from arylamine carcinogens: fluorinated 2-aminofluorene (FAF), 2-acetylaminofluorene (FAAF), and 4-aminobiphenyl (FABP). Tight polymerase binding was detected with unmodified dG and the correct dCTP. The discrimination of correct versus incorrect nucleotides was pronounced with KD values in order of dCTP << dTTP < dATP < dGTP. In contrast, minimal selectivity was observed for the modified templates with Kf-exo- binding tighter to the FAAF (koff: 0.02s-1) and FABP (koff: 0.01s-1) lesions than to FAF (koff: 0.04s-1).
Chemical research in toxicology.Chem Res Toxicol.2012 Jul 17. [Epub ahead of print]
We used surface plasmon resonance (SPR) to characterize the binding interactions between exonulease-free Klenow fragment (Kf-exo-) and unmodified and modified dG adducts derived from arylamine carcinogens: fluorinated 2-aminofluorene (FAF), 2-acetylaminofluorene (FAAF), and 4-aminobiphenyl (FABP). T
PMID 22804627

Japanese Journal

Resveratrol Downregulates Cyp2e1 and Attenuates Chemically Induced Hepatocarcinogenesis in SD Rats

Wu Xiongfei,Li Chenggang,Xing Guozhen [他],Qi Xinming,Ren Jin
Journal of Toxicologic Pathology 26(4), 385-392, 2013
… Resveratrol (REV) is known to prevent diethylnitrosamine (DEN)-induced hepatocarcinogenesis, but its effects on this process induced by DEN and 2-acetylaminofluorene (2-AAF) and the role of Cyp2e1 remain unclear. …
NAID 130003382457

Development of a Medium-term Animal Model Using gpt Delta Rats to Evaluate Chemical Carcinogenicity and Genotoxicity

Matsushita Kohei,Kijima Aki,Ishii Yuji [他],Takasu Shinji,Jin Meilan,Kuroda Ken,Kawaguchi Hiroaki,Miyoshi Noriaki,Nohmi Takehiko,Ogawa Kumiko,Umemura Takashi
Journal of Toxicologic Pathology 26(1), 19-27, 2013
… The genotoxic carcinogens 2-acetylaminofluorene (2-AAF), 2-amino-3-methylimidazo [4,5-f] quinolone (IQ) and safrole (SF), the non-genotoxic carcinogens piperonyl butoxide (PBO) and phenytoin (PHE), the non-carcinogen acetaminophen (APAP) and the genotoxic non-hepatocarcinogen aristolochic acid (AA) were tested to validate the GPG46 model. …
NAID 130003362353

Urinary Bladder Carcinogenesis by DNA Reactive and Non-Reactive Chemicals : Non-Linearities and Thresholds

Cohen Samuel M.
Genes and environment : the official journal of the Japanese Environmental Mutagen Society 34(4), 165-170, 2012-11-20
NAID 10031125865

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★リンクテーブル★

リンク元	「2-AAF」「アセチルアミノフルオレン」
拡張検索	「2-acetylaminofluorene」「acetoxyacetylaminofluorene」「hydroxyacetylaminofluorene」

「2-AAF」

2-Acetylaminofluorene
Names
	Systematic IUPAC name N-(9H-fluoren-2-yl)acetamide
	Other names 2-Acetaminofluorene; N-2-Fluorenylacetamide; N-Acetyl-2-aminofluorene
Identifiers
CAS Number	53-96-3
Abbreviations	2-AAF
Beilstein Reference	2807677
ChEBI	CHEBI:17356
ChEMBL	ChEMBL311469
ChemSpider	5686
EC Number	200-188-6
	InChI InChI=1S/C15H13NO/c1-10(17)16-13-6-7-15-12(9-13)8-11-4-2-3-5-14(11)15/h2-7,9H,8H2,1H3,(H,16,17) Key: CZIHNRWJTSTCEX-UHFFFAOYSA-N ; InChI=1/C15H13NO/c1-10(17)16-13-6-7-15-12(9-13)8-11-4-2-3-5-14(11)15/h2-7,9H,8H2,1H3,(H,16,17) Key: CZIHNRWJTSTCEX-UHFFFAOYAF ;
Jmol interactive 3D	Image; Image
KEGG	C02778
MeSH	2-Acetylaminofluorene
PubChem	5897
RTECS number	AB9450000
	SMILES CC(=O)Nc1ccc2c(Cc3ccccc23)c1 ; CC(=O)NC1=CC=C2C(CC3=C2C=CC=C3)=C1 ;
UN number	3077
Properties
Chemical formula	C15H13NO
Molar mass	223.28 g·mol−1
Appearance	Vivid, light brown, opaque crystals
Melting point	192 to 196 °C (378 to 385 °F; 465 to 469 K)
log P	3.264
Hazards
Main hazards	potential occupational carcinogen
GHS pictograms
GHS signal word	Danger
GHS hazard statements	H302, H350
GHS precautionary statements	P201, P308+313
EU classification (DSD)	T N
R-phrases	R45, R22, R51/53
S-phrases	S53, S36/37/39, S45
	US health exposure limits (NIOSH):
PEL (Permissible)	[OSHA-Regulated Carcinogen]
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	verify (what is ?)
	Infobox references

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2-アセチルアミノフルオレン

関: 2-acetylaminofluorene、acetylaminofluorene

「アセチルアミノフルオレン」

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英: acetylaminofluorene
関: 2-アセチルアミノフルオレン

「2-acetylaminofluorene」

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2-アセチルアミノフルオレン

関: 2-AAF、acetylaminofluorene

「acetoxyacetylaminofluorene」

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アセトキシアセチルアミノフルオレン

「hydroxyacetylaminofluorene」

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ヒドロキシアセチルアミノフルオレン

[pocket-1] "NIOSH Pocket Guide to Chemical Hazards". Centers for Disease Control and Prevnetion.

[NIOSH-2] "NIOSH Pocket Guide to Chemical Hazards #0007". National Institute for Occupational Safety and Health (NIOSH).

[3] "2-Acetylaminofluorene - PubChem Public Chemical Database". The PubChem Project. USA: National Center for Biotechnology Information. Descriptors Computed from Structure.

[loganabbrev-4] Logan, Carolynn M.; Rice, M. Katherine (1987). Logan's Medical and Scientific Abbreviations. Philadelphia: J. B. Lippincott Company. p. 3. ISBN 0-397-54589-4.

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案内

案内

acetylaminofluorene