Reaction of esters of aromatic -hydroxy amines and amides with methionine : A model for binding of amine carcinogens to protein

Lotlikar, Prabhakar D.; Scribner, John D.; Miller, James A.; Miller, Elizabeth C.

doi:10.1016/0024-3205(66)90026-9

Cited by 126 publications

(41 citation statements)

References 9 publications

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“…2-Aminofluorene (22), N-hydroxy-2-acetylaminofluorene (23), N-acetoxy-2-acetylaminofluorene (24), N-hydroxy-2-aminofluorene (23), and 2-nitrosofluorene (25) were prepared by the methods cited in the references. 2-Acetylaminofluorene (Schwarz-Mann) and 2,7-bis-acetylaminofluorene (Schuchardt) were crystallized from ethanol; 2-nitrofluorene (Aldrich) was purified by chromatography on aluminum oxide and crystallization from dichloromethanehexane.…”

Section: Methodsmentioning

confidence: 99%

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Ames

Gurney

Miller

et al. 1972

Proc. Natl. Acad. Sci. U.S.A.

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301

121

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Several carcinogenic metabolites of the carcinogen 2-acetyl-aminofluorene, especially 2-nitrosofluorene and N-hydroxy-2-aminofluorene, are potent frameshift mutagens for Salmonella typhimurium. 2-Nitrosonaphthalene, 2-nitrosophenanthrene, 4-nitroso-transstilbene, 4-nitrosobiphenyl, and 4-nitrosoazobenzene, all of which are metabolites or likely metabolites of carcinogenic aromatic amines, are also potent frameshift mutagens. These compounds may be frameshift mutagens of the class that intercalates into DNA and then reacts covalently with the DNA; various ultimate carcinogens may be of this type. The utility of a set of bacterial strains for detecting carcinogens as mutagens is shown.Various planar polycyclic aromatic compounds, such as the acridines, which can intercalate in the DNA base-pair stack (1-9), are mutagens that cause additions or deletions of nucleotides (10-12). These errors appear to result from stabilization of a shifted pairing in a repetitive sequence in DNA by intercalation of the planar compound and subsequent addition or deletion of base pairs during replication or repair synthesis (11,13). Mlutagens with this property are called frameshift mutagens because of the shift in the reading frame of the mRNA synthesized from the altered DNA template; thus they differ from mutagens that cause basepair substitutions (11). The potency of an intercalating agent as a frameshift mutagen may increase by 10-to 100-fold if it also contains a side chain that can react covalently with DNA (12,(14)(15)(16)(17).Since it seemed possible that the reactive forms of some carcinogens with planar ring systems could be frameshift mutagens that both intercalate and react with DNA, epoxides of polycyclic hydrocarbons were examined and found to be mutagens of this type (16). In this paper this question is examined further with certain known and potential metabolites of 2-acetylaminofluorene (18). The striking activity of 2-nitrosofluorene as a frameshift mutagen then led to tests of nitroso derivatives related to various other aromatic amine carcinogens. These studies have made use of a set of tester strains (14-16) of Salmonella typhimurium that were developed for detection and classification of mutagens. MATERIALS AND METHODSBacterial Test for Mutagens. The mutagenicity test uses four Salmonella strains that require histidine (14-16). The test measures the effect of a mutagen on the reversion to growth on a histidine-free medium of these tester strains. Three of the tester strains (TA1531, TA1532, and TA1534) were designed for detecting frameshift mutagens with different specificities; each strain has a frameshift mutation in one of the genes of the histidine operon. The fourth strain (TA1530) has a base-pair change in the histidine G gene, and is used to detect mutagens that cause base-pair substitutions. In addition, all four strains lack the excision repair system (because of a deletion through uvrB); this makes them much more sensitive to any mutagen that alters the DNA in a way that would normally be repai...

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Section: Methodsmentioning

confidence: 99%

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Ames

Gurney

Miller

et al. 1972

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

301

121

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“…N-Acetoxy-2-acetylaminofluorene (N-acetoxy-AAF) was synthesized as described (19) and supplied by R. Gentles (SUNY, Stony Brook, NY). Oligonucleotides were synthesized as reported (20).…”

Section: Methodsmentioning

confidence: 99%

Acetylaminofluorene and aminofluorene adducts inhibit in vitro transcription of a Xenopus 5S RNA gene only when located on the coding strand.

Chen

Matsumoto

Shibutani

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Unique N-acetyl-2-aminofluorene (AAF) or 2-aminofluorene (AF) adducts were introduced into the Xenopus borealis somatic 5S RNA gene between the intragenic control region and the transcription termination site. The effects of these bulky adducts on transcription were studied in a cell-free extract derived from Xenopus laevis oocytes. AAF and AF adducts inhibit transcription only when they are on the template strand, whereas transcription passes through these adducts when they are placed on the nontemplate strand. In the presence of the AAF or AF adduct on the template strand, transcription usually terminates one nucleotide before the altered guanine residue. Premature termination at these bulky adducts does not block reinitiation of transcription, since several transcripts are produced per gene per hour on these damaged templates.

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“…Analogous studies with N-acetoxy-AAF showed that it had similar, but stronger, electrophilic reactivity. Thus, N-acetoxy-AAF reacted at neutrality with methionine to yield 1-and 3-methylmercapto-AAF (72) and with guanine residues in nucleosides or polynucleotides (73,74); under appropriate conditions nearly all of the guanine residues in DNA or RNA could be modified. N-Benzoyloxy-MAB and Nacetoxy-AAF proved to be carcinogenic in the subcutaneous tissue of rats, a site where the respective parent compounds MAB and AAF did not produce tumors (71,75).…”

Section: Discovery Of Metabolically Derived Electrophilic Noderivativesmentioning

confidence: 99%

Some historical aspects of N-aryl carcinogens and their metabolic activation.

Miller¹,

Miller²

1983

Environ Health Perspect

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This limited review of the early studies on the activation of the N-aryl carcinogens was written to provide a background for the current research to be presented at this conference on carcinogenesis by N-aryl compounds. Since the work of the past 10 years is too recent to be judged in a historical sense and because those data are much better known by current investigators, this review is generally limited to data up to 1972.

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Reaction of esters of aromatic -hydroxy amines and amides with methionine : A model for binding of amine carcinogens to protein

Cited by 126 publications

References 9 publications

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens

Acetylaminofluorene and aminofluorene adducts inhibit in vitro transcription of a Xenopus 5S RNA gene only when located on the coding strand.

Some historical aspects of N-aryl carcinogens and their metabolic activation.

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