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Biomedical subjects

E Kriek

Publications and source records attributed to E Kriek.

At least 55 records · Page 3Linked to original sources
PubMed1981

Induction of chromosomal aberrations and sister-chromatid exchanges in Chinese hamster cells in vitro by some proximate and ultimate carcinogenic arylamide derivatives.

The carcinogenic compounds N-hydroxy-N-acetyl-2-aminofluorene, N-acetoxy-N-acetyl-2-aminofluorene, N-hydroxy-N-acetyl-4-aminobiphenyl and N-acetoxy-N-acetyl-4-aminobiphenyl were studied for their ability to induce chromosomal aberrations and sister-chromatic exchanges in Chinese hamster ovary cells in the presence and absence of a rat-liver microsomal system. The O-acetates of N-hydroxy-N-acetyl-2-aminofluorene and N-hydroxy-N-acetyl-4-aminobiphenyl induced chromosomal aberrations in a population of cells samples at 22--25 h after treatment. The N-hydroxy arylacetamides did not produce detectable increases in chromosomal aberrations when tested at 22--25 h after treatment, but micronuclei that had arisen from acentric fragments at the first mitosis were demonstrable in second-division cells fixed between 30 and 33 h after treatment. N-Acetoxy-N-acetyl-2-aminofluorene appeared to be a more effective inducer of chromosomal damage than the corresponding biphenyl derivative. All O-acetates and N-hydroxy derivatives induced sister-chromatid exchanges. N-Acetoxy-N-acetyl-4-aminobiphenyl and N-hydroxy-N-acetyl-4-aminobiphenyl were equally effective, whereas N-acetoxy-N-acetyl-2-aminofluorene was a better inducer of sister-chromatid exchanges than N-hydroxy-N-acetyl-2-aminofluorene. Simultaneous treatment of cells with O-acetates and S9 mix decreased the effectivity to induce chromosomal damage as compared to treatment with O-acetates alone. In one experiment where the organic solvent DMSO was used at the concentration of 10% in combination with S9 mix, substantial amounts of chromosomal aberrations were induced.

Acetoxyacetylaminofluorene↗
PubMed1981

Formation of N-2-fluorenylhydroxylamine adducts of DNA in vivo and in vitro and some of their properties.

The major 2-fluorenylamine-DNA derivative formed in vivo in rat liver after application of N-2-flourencylacetamide is N-(deoxyguanosin-8-yl)-2-fluorenylamine. This nucleoside, hydrolyzed under mild alkaline conditions with the opening of the imidazole ring, formed two pyrimidine derivatives which can be separated by Sephadex LH-20 column chromatography and thin-layer chromatography on silica. The hydrolysis reaction was catalyzed by metal ions and alkaline phosphatase from Escherichia coli.

2-Acetylaminofluorene↗
PubMed1980

Circular dichroism and proton magnetic resonance studies of dApdG modified with 2-aminofluorene and 2-acetylaminofluorene.

The conformational properties of 2'-deoxyadenylyl-(3'-5')-2'-deoxyguanosine (dApdG) modified by the covalent binding of the carcinogens 2-acetylaminofluorene (AAF) and 2-aminofluorene (AF) have been investigated, utilizing circular dichroism and proton magnetic resonance spectroscopy. The attachment of AF residues to the C-8 position of guanosine introduced smaller changes in the circular dichroism spectra of dApdG than the binding of AAF residues. Similarly, binding of AF residues caused lower up-field shifts for the H-2 and H-8 protons of adenine than the AAF residues. These results suggest that AF residues are less stacked with the neighboring A base in dApdG than AAF. Thus, AF residues bound on the C-8 position of guanine might induce less distortion in conformation of the modified regions than AAF residues.

2-Acetylaminofluorene↗
PubMed1980

Structural identification of the pyrimidine derivatives formed from N-(deoxyguanosin-8-yl)-2-aminofluorene in aqueous solution at alkaline pH.

The major aminofluorene-DNA derivative formed from the carcinogen N-acetyl-2-aminofluorene in vivo in rat liver is N-(deoxyguanosin-8-yl)-2-aminofluorene. This nucleoside is hydrolyzed in aqueous solution at alkaline pH through the 7-8 guanine bond to form two pyrimidine derivatives which were separated by Sephadex LH-20 column chromatography and thin-layer chromatography on silica. From chemical, u.v., i.r., n.m.r. and mass spectral analysis the pyrimidine derivatives have been identified as 1-[6-(2,5-diamino-4-oxopyrimidinyl-N6-deoxyriboside)]-3-(2-fluorenyl)ureas, which probably are stereoisomers. Similar products were isolated from enzymatic hydrolysates of DNA reacted with N-hydroxy-2-aminofluorene under mildly acidic conditions (pH 5) and subsequent treatment with 0.1 N NaOH. Kinetic studies of the hydrolysis reaction showed that it occurs already at a measurable rate at pH 9.5 and 37 degrees C. The reaction is catalyzed by Mg2+ and Mn2+ ions and by alkaline phosphatase from E. coli.

2-Acetylaminofluorene↗
PubMed1979

Effect of pH on the ratio of substitution products in DNA after reaction with the carcinogen N-acetoxy-2-acetylaminofluorene.

The substitution reaction products of N-acetoxy-2-acetylaminofluorene (N-AcO-AAF) and the N-sulfate (potassium salt) of N-hydroxy-4-acetyl-aminobiphenyl (N-OSO3K-AABP) with DNA from calf thymus were determined after reaction in buffered solutions of 0.10 M NaCl at pH values from 4--9. In the case of N-AcO-AAF, the ratio of N-(guanin-8-yl)-2-acetylaminofluorene (N-(guanine-8-yl)-AAF) to 3-(guanin-N2-yl)-2-acetylaminofluorene (3-(guanin-N2-yl)-AAF) increased 2.2 times over the entire pH range studied, starting at pH 9. With the N-OSO3K-AABP, the total substitution of guanine was much lower (22--34 times) as compared with N-AcO-AAF, and the ratio of N-(guanin-8-yl)-4-acetylaminobiphenyl to 3-(guanin-N2-yl)-4-acetylaminobiphenyl was not affected by a change in pH of the reaction medium. As expected, heat-denatured DNA reacted more extensively with both esters, but an increase in substitution was much more pronounced for the biphenyl derivative (9 times) than for the fluorene compound (2.8 times). Degradation, denaturation or interstrand cross-linking of DNA were not observed under the reaction conditions employed.

2-Acetylaminofluorene↗
PubMed1979

Differential excision from DNA of the C-8 deoxyguanosine reaction products of N-hydroxy-2-aminofluorene and N-acetoxy-N-acetyl-2-aminofluorene by endonuclease S1 from Aspergillus oryzae.

Calf thymus DNA was modified in vitro with [G-3H]N-hydroxy-2-aminofluorene and [G-3H]N-acetoxy-N-acetyl-2-aminofluorene and the nuclease S1 digestion was studied under identical conditions. The ratios of the maximum reaction rate (V) and the Michaelis constant (Km), V/Km, indicate that 2-aminofluorene(AF)-modified DNA is hydrolyzed 3 times more slowly than N-acetyl-2-aminofluorene(AAF)-modified DNA under similar reaction conditions. The AF-modified DNA was slightly more susceptible to partial digestion by nuclease S1 than unmodified control DNA. These results suggest that the local regions of denaturation induced by AF substitution are smaller than those associated with AAF modification.

2-Acetylaminofluorene↗
PubMed1978

Reaction products of the carcinogen N-hydroxy-4-acetylamino-4'-fluorobiphenyl with DNA in liver and kidney of the rat.

The binding of AABP4'F and ABP4'F residues to rat liver and kidney DNA in vivo was studied at different periods of time after administration of N-[G-3H]hydroxy-AABP4'F at dose levels of 5 and 25 mg/kg body weight. DNA preparations from both organs were hydrolyzed enzymatically at pH 8--9 with mixtures of DNAase, snake venom phosphodiesterase and alkaline phosphatase from Escherichia coli. The enzymatic digests were analysed by Sephadex LH-20 chromatography using synthetic N-([G-14C] deoxyguanosin-8-yl)-AABP4'F as marker. Elution with 30% ethanol gave three major peaks of tritium activity. The first peak consisted largely of N-(deoxyguanosin-8-yl)-ABP4'F decomposition products, which were not further characterized. The second product has similar chromatographical and chemical properties as 3-(deoxyguanosin-N2-yl)-AAF; and was also persistent in liver as well as in kidneys. The third peak of tritium activity co-chromatographed with the marker compound N-([G-14C] deoxyguanosin-8-yl)-AABP4'F. Kinetic studies revealed that the latter product was removed rapidly from liver and kidney DNA at equal rates (t1/2 = 2 days). Approximately 80% of the total radioactivity bound to DNA consisted of deacetylated material, which was removed at a much slower rate (t1/2 = 10 days) in both organs. An initial rapid removal of all products in kidney during the first 7 days (t1/2 = 3.3 days) at dose levels of 25 mg/kg is probably due to toxic effects on the kidneys, because this phenomenon was not observed at dose levels of 5 mg/kg. The synthetic ester N-OSO3K-AABP4'F was at least twice as reactive towards L-methionine and guanosine as compared to the corresponding AABP derivative, but had 40% of the reactivity of N-acetoxy-AAF under similar conditions. The new compounds 3-methylmercapto-4-acetylamino-4'-fluorobiphenyl and N-(deoxyguanosin-8-yl)-4-acetylamino-4'-fluorobiphenyl have been characterized by means of their NMR and mass spectra. Attempts to devise an unambiguous synthesis for 3-(deoxyguanosin-N2-yl)arylamides have been unsuccessful.

2-Acetylaminofluorene↗
PubMed1976

Identification of the persistently bound form of the carcinogen N-acetyl-2-aminofluorene to rat liver DNA in vivo.

In this article the structural analysis of the persistently bound form of the carcinogen N-acetyl-2-aminofluorene (AAF) to rat liver DNA in vivo is described. This compound appears to result from the formation of a covalent bond between carbon-3 of the aromatic ring and the amino group of guanine. Experimental evidence from three different approaches had led to the identification of the structure of the persistently DNA-bound AAF moiety. First, [3-3H, 9-14C]N-acetoxy-AAF was reacted with DNA in vitro. As reported previously, a minor product was isolated from enzymatic digests of the reacted DNA, which had chemical and chromatographic properties identical to those of the persistent--AAF moiety in DNA in vivo. The ratio 3H/14C of this product had diminished to the same extent as 3-CH3S-AAF resulting from the reaction of methionine with [o-3H, 9-14C]N-acetoxy-AAF. Secondly, reaction of [9-14C]N-acetoxy-AAF with DNA, which was tritiated in the C-8 positions of the purines, did not result in removal of tritium in the persistent fraction obtained after acid hydrolysis, thus excluding substitution at C-8 and N-7 of guanine. Finally , by reacting N-OSO3-K-AAF with deoxyguanosine in dimethylsulfoxide-triethylamine, a compound could be isolated, which was identified as 3-(deoxyguanosin-N2-yl)-AAF based on its NMR spectrum and on the mass spectrum of the corresponding guanine derivative obtained after removing deoxyribose by acid hydrolysis. This compound appeared to be identical with the persistently bound form present in DNA hydrolysates from rat liver after injection of [2'-3H]N-hydroxy-AAF.

2-Acetylaminofluorene↗