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PubMed1988

The preparation of a partially protected heptasaccharide-asparagine intermediate for glycopeptide synthesis.

The heptasaccharide O-alpha-D-mannopyranosyl-(1----6)-O-[alpha-D-mannopyranosyl-(1----3)]-O- alpha-D-mannopyranosyl-(1----6)-O-[alpha-D-mannopyranosyl-(1----3)]-O-be ta- D-mannopyranosyl-(1----4)-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)- (1----4)-2-acetamido-2-deoxy-D-glucopyranose, isolated from the urine of swainsonine-intoxicated sheep, was peracetylated and was converted into the glycosyl azide by three alternative procedures, the most successful of which was formation of peracetyl oxazoline by treatment with trimethylsilyl trifluoromethanesulfonate, followed by treatment with trimethylsilyl azide. Reduction of the glycosyl azide in the presence of Lindlar catalyst gave the glycosylamine derivative, which was coupled with 1-benzyl N-fluoren-9-ylmethoxycarbonyl-L-aspartate to yield a protected glycosylasparagine. The benzyl ester group was easily removed by hydrogenolysis to form an intermediate suitable for glycopeptide synthesis.

Asparagine↗
PubMed1979

Quantitative and qualitative aspects of the binding of N-hydroxy-2-acetylaminofluorene to hepatic chromatin fractions.

The binding of a chemical carcinogen to components of hepatic chromatin in male rats was examined. After a single injection of N-[3H]hydroxy-2-acetylaminofluorene ([3H]OH-AAF) covalent binding to chromatin RNA, protein, and DNA occurs. The amount of carcinogen bound to RNA was approximately 5 times greater than to DNA, and 10 times that of the protein. However, loss of carcinogen from RNA with time was rapid, whereas a persistent binding to DNA equal to 15% of the initial values was observed. To localize the initial and persistent DNA-bound carcinogen, the genome was fractionated using two different chromatin fractionation procedures. The procedures used yielded 3 chromatin fractions based on physical characteristics, degree of association with nascent RNA and in vitro template capacity. Based on those parameters, these chromatin fractions have been tentatively classified as template expressed euchromatin, a repressed heterochromatin, and a highly condensed pelleted heterochromatin. With both the glycerol gradient chromatin fractionation procedure and the selective MgCl2 chromatin precipitation procedure, the initial (2 h) binding of carcinogen was greatest on the euchromatin DNA. Loss of carcinogen from the DNA, however, was also significantly faster from the euchromatin when compared to the heterochromatin and the pelleted heterochromatin. By 10 days after a single injection of the carcinogen, the largest amount of bound fluorene residues was located on the pelleted heterochromatin DNA, an apparently repressed portion of the genome, while less than 5% of the initial values were found on either the eu- or heterochromatin. When the rats were fed a 2-acetylaminofluorene-containing diet, loss of carcinogen from the pelleted heterochromatin DNA was enhanced, while loss from the euchromatin DNA was reduced. The covalent nature of the carcinogen modification of DNA was confirmed by thin-layer chromatography (TLC). These studies also demonstrated 2 separate carcinogen-purine base adducts which were identified as N-(guanin-8-yl)-N-AF and 3-(guanin-N2-yl)-N-AAF based on either co-chromatography with an authentic standard or on published Rf-values, respectively. The pelleted heterochromatin DNA had a significantly greater proportion of the 3-guanine-N2 adduct when compared to DNA from either the eu- or heterochromatin.

2-Acetylaminofluorene↗
PubMed1980

Tissue binding of 2-acetylaminofluorene in BAlB/c and C57Bl/6 mice during chronic oral administration.

Blood and tissue binding levels of [9-14C]2-acetylaminofluorene ([9-14C]2-AAF) administered in the diets of female BALB/c and C57Bl/6 mice, were determined. Blood and liver levels reached a plateau after 2--4 weeks, while levels in bladder tissue continued to increase. Binding levels two weeks administration were determined in liver, bladder, kidney, lung, spleen, heart and skeletal muscle. In every instance the binding was linear over a dose range of 0.5--500 ppm 2-AAF. Removal of the 2-AAF in the diet after 48 weeks resulted in a rapid loss of radioactivity from blood and liver, with little or no loss from bladder tissue. The linear dose-response relationship of tissue binding correlated well with the previously reported linear dose response curve for liver tumors but did not correlated with the reported non-linear dose response curve for bladder tumors. A reversed correlation was found in the ability of the tissue to remove bound fluorene residues and the observed rate of tumor occurrence following discontinued administration of the carcinogen.

2-Acetylaminofluorene↗
PubMed1995

Induction of Cyp1a-1 and Cyp1a-2 gene expression by a reconstituted mixture of polynuclear aromatic hydrocarbons in B6C3F1 mice.

The potential non-additive interactions of polynuclear aromatic hydrocarbon (PAH) mixtures as inducers of Cyp1a-1 and Cyp1a-2 gene expression were investigated in B6C3F1 mice using a reconstituted PAH mixture. The chemical composition (% by weight) of the reconstituted PAH mixture was: 2-ring PAHs--indan (0.22), naphthalene (23.8), 2-methylnaphthalene (23.2) and 1-methylnaphthalene (13.3); 3-ring PAHs--acenaphthylene (7.7), acenaphthene (0.6), dibenzofuran (0.7), fluorene (4.3), phenanthrene (10.5) and anthracene (3.4); > or = 4-ring PAHs--fluoranthene (2.4), pyrene (4.3), benz[a]anthracene (1.4), chrysene (1.5), benzo[b]fluoranthene (0.8), benzo[k]fluoranthene (0.9) and benzo[a]pyrene (0.9). The composition of the 2-, 3- and > or = 4-ring PAH fractions were based on the relative concentration of individual PAHs as noted above. The > or = 4-ring PAH fractions were based on the relative concentration of individual PAHs as noted above. The > or = 4-ring PAH fraction and reconstituted mixture induced hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity and Cyp1a-1 mRNA levels, whereas the 2- and 3-ring PAHs were only weakly active. Direct comparison of the potencies of the reconstituted mixture and > or = 4-ring PAHs showed that the Cyp1a-1 induction activity of the reconstituted mixture was due to the > or = 4-ring PAHs. The reconstituted PAH mixture and > or = 4-ring PAHs also induced Cyp1a-2 hepatic mRNA levels and microsomal methoxyresorufin O-deethylase (MROD) activity; however, their dose-response curves indicated that the reconstituted PAH mixture was more potent as a Cyp1a-2 inducer than the > or = 4 ring PAHs. The differences in potency were due to 3-ring PAHs which were found to be strong inducers of hepatic Cyp1a-2 mRNA levels and microsomal MROD activity at the lowest dose administered (37 mg/kg). The 3-ring mixture caused a maximal 29-fold increase in hepatic MROD activity at a dose of 292 mg/kg, but only 28% of maximal induction of EROD activity. Northern analysis of liver mRNA from mice treated with 3-ring PAHs showed that there was minimal induction of Cyp1a-1 mRNA levels. The 3-ring PAHs did not competitively bind to the mouse hepatic cytosolic aryl hydrocarbon (Ah) receptor suggesting that 3-ring PAHs are a new class of Cyp1a-2 inducers which do not act through the Ah receptor.

Animals↗
PubMed1995

Lipopolysaccharide determination by reversed-phase high-performance liquid chromatography after fluorescence labeling.

A sensitive method for the quantitative determination of lipid A, the covalently bound hydrophobic component of lipopolysaccharides (endotoxins), has been developed. The determination of lipid A was based on the quantitative measurement of beta-hydroxymyristic acid and beta-hydroxylauric acid by reversed-phase HPLC. beta-Hydroxy acids were liberated from ester and amide linkages in endotoxins by acid catalyzed methanolysis. The resulting methyl esters were derivatized with 9-anthracene-carboxyl chloride, 9-fluorene-carboxyl chloride and 4-(1-pyrenyl)butyric acid chloride and quantified with a fluorescence detector. The effectiveness of the three derivatizing agents was compared. As internal standards-beta-hydroxytridecanoic acid [beta-OH(13:0)] and beta-hydroxypentadecanoic acid [beta-OH(15:0)] ethyl esters were used. The limits of detection of beta-hydroxymyristic acid were 0.5 pg for the 9-anthroyl and 2 pg for the fluorenoyl and 4-(1-pyrenyl)butyroyl ester per sample (signal-to-noise ratio of 3). The detection limits of lipopolysaccharide from a smooth strain (Escherichia coli 0111:B4) was 20 pg, while that from two rough strains (E. coli Nissle 1917 and Salmonella typhimurium SL 1181) was 5 pg per sample after methanolysis and derivatization with 9-anthroyl chloride.

Chromatography, High Pressure Liquid↗
PubMed1986

Specificity of N-acetoxy-N-2-acetylaminofluorene-induced frameshift mutation spectrum in mismatch repair deficient Escherichia coli strains mutH, L, S and U.

The mismatch repair system of Escherichia coli is known to contribute to the fidelity of the replicational process. This system involves the functions of mutH, mutL, mutS and mutU (uvrD) loci which recognize mispaired bases as a consequence of errors due to the polymerase itself. Chemical modifications of DNA have also been suspected to create mispaired bases which, if the mispaired bases are removed, will lead to mutations by frameshift. Using the pBR322 plasmid DNA modified by the ultimate carcinogen N-acetoxy-N-2-acetylaminofluorene (N-Aco-AAF) we have investigated this possibility in a forward mutational assay (tetracycline sensitivity). This fluorene derivative has been shown to induce predominantly frameshift mutations. Our results show that: The sensitivity of the deficient strains mutH, mutL and mutS to the AAF adducts is similar to that of the corresponding wild-type strain. However, the mutU strain appears much more sensitive to those adducts although less than a uvrA, B or C-deficient strain. This suggests that the mutU gene product is involved in the repair of AAF adducts. For the four mut deficient strains, and as it was shown with the wild-type strain, AAF adducts induced mutations to tetracycline sensitivity are only observed when the SOS system of the host bacteria is induced by irradiation of the cells prior to transformation with the modified plasmid. The mutation frequencies depend upon the ultraviolet light doses and similar maxima were found for the four mut strains and the corresponding wild-type strain. In agreement with the results obtained with wild-type or uvrA strains we observe that AAF adducts induce mostly frameshift mutations in the mut strains. Two types of hot spots of mutagenesis were described in wild-type and uvrA strains occurring either at repetitive sequences or at sequences of the type 5' G-G-C-G-C-C 3' (NarI restriction enzyme recognition sequence). While the second type of mutational hot spot does exist in the mismatch repair-deficient strains, we observe that the repetitive sequences are no longer hot spots of mutations in these strains, suggesting that the mismatch repair protein complex is involved in the establishment of AAF-induced frameshift mutations at repetitive sequences.

2-Acetylaminofluorene↗
PubMed1988

An isolated perfused model for the study of colonic metabolism and transport.

The murine colonic perfusion model allows for the examination of absorption, metabolism, and portal transfer by the colon under physiologic conditions. This model was characterized by the use of four radiolabeled compounds: estradiol and Vitamin D3, both physiologically active circulating steroid compounds, and benzo[a]pyrene and N-acetylaminofluorene, xenobiotic carcinogens of the aromatic hydrocarbon and aromatic amide classes, respectively. Hemodynamic parameters and oxygen consumption of the preparation were stable throughout perfusion. Estradiol and N-acetylaminofluorene entered the portal vein at a rate of 2% of the lumenal dose per hour. Benzo[a]pyrene crossed at 0.4% of the lumenal dose per hour. The rate of transfer of Vitamin D3 was negligible. Analysis of the lumenal label revealed only substrate. In all experiments less than 0.02% of the applied substrate remained in the tissue compartment. Analysis of the vascular perfusate demonstrated evidence for sulfates of estradiol and N-acetylaminofluorene. Three conjugate classes were found associated with benzo[a]pyrene, constituting 42% of the portal label. Hydrolysis data suggests the presence of double conjugates of benzo[a]pyrene involving glutathione. In the case of aromatic hydrocarbons, conjugation, particularly thioether formation, implies hydroxylation and epoxide formation. For sulfation an N-acetylamino-fluorene ring or N-hydroxylation is required. The latter process could allow for the delivery of highly carcinogenic N-O sulfates to the liver.

2-Acetylaminofluorene↗
PubMed1995

Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes.

The effects of flavonols on P-glycoprotein (Pgp) activity were studied in cultured rat hepatocytes by assessing and transmembrane transport of Rhodamine-123 (R-123) and doxorubicin (DOX). In freshly-plated hepatocytes, containing a low amount of Pgp, flavonols did not affect the cellular retention of DOX, but strongly inhibited the Pgp-mediated efflux of R-123. In 72h-cultured hepatocytes, spontaneously overexpressing functional Pgp, flavonols inhibited R-123 efflux in a dose-dependent manner, but significantly reduced DOX retention while increasing its efflux. A similar effect was found in hepatocytes obtained from rats in which Pgp was induced in vivo by 2-acetamino-fluorene (AAF) or alpha-naphthyl-isothiocyanate (ANIT) treatments. These findings indicate that flavonols, dietary compounds reported to strongly upregulate the apparent activity of Pgp in cancer cell lines, may also modulate differently the transport of putative Pgp substrates in normal rat hepatocytes. The ability to affect the drug-extruding activity at the hepatocyte canalicular membrane could be of relevance to the chemopreventive action of these compounds towards liver carcinogens.

2-Acetylaminofluorene↗
PubMed1991

Transformation of arylamines into direct-acting mutagens by reaction with nitrite.

Arylamines including aniline (I), 1-naphthylamine (II), 2-naphthylamine (III), 2-aminofluorene (IV), 1-aminoanthracene (V) and 1-aminopyrene (VI) were treated with 4 equivalent amounts of nitrite at pH3 and 37 degrees C for 4 h. The reaction mixtures of I, IV, V and VI showed mutagenicity to Salmonella typhimurium TA98 and TA100 strains without metabolic activation. The numbers of His+ revertant colonies to TA98 strain were 110/0.05 mumole I, 970/0.055 mumole IV, 620/0.10 mumole V and 870/0.02 mumole VI. These arylamines were converted into mutagens with diazoquinone, diazonium and nitro functions depending on their structures. The mutagen from I was p-diazoquinone (I2). The mutagen from IV was highly unstable fluorene-2-diazonium salt (IV1). The mutagens from V were N3O3-introduced anthracene (V1-1) and 1-nitroanthracene (V2), and those from VI were unidentified nitro-introduced compound (VI1) and 1-nitropyrene (VI2).

1-Naphthylamine↗
PubMed1983

Involvement of alpha- and beta 1-adrenergic mechanisms in the immobility-reducing action of desipramine in the forced swimming test.

The influences of various monoaminergic agents on the immobility-reducing action of desipramine (DMI) in the forced swimming test were examined. 5-Methoxy-N,N-dimethyltryptamine and methysergide, a serotonin agonist and antagonist, respectively, did not affect the duration of immobility. Pimozide, a dopamine antagonist, prolonged the duration of immobility at a dose of 0.5 mg/kg. However, at the doses tested, these drugs had no effect on the action of desipramine. Phenoxybenzamine, an alpha-adrenergic antagonist, prolonged the duration of immobility only with the largest dose (20 mg/kg), but the action of desipramine was completely blocked by this drugs at all doses. Intracerebroventricular injection of a beta-adrenergic agonist, isoproterenol (ISO), and two selective beta 1-adrenergic antagonists, atenolol (ATE) and practolol, dose-dependently diminished and potentiated, respectively, the action of desipramine although these drugs had no effect on the duration of immobility when given alone. A beta 2-adrenergic antagonist derived from oximino-9-fluorene, (IPS 339) did not influence the duration of immobility or affect the action of desipramine. The effect of isoproterenol was almost completely blocked by the pretreatment with atenolol and practolol but not by IPS 339. Subcutaneously-injected isoproterenol did not affect the action of desipramine. Isoproterenol and atenolol had no effect on the concentration of desipramine in brain regions. Phenylephrine, a postsynaptic alpha-adrenergic agonist, reduced the duration of immobility as did desipramine, but this action was not affected by isoproterenol and atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

The effect of aging on sister chromatid exchange.

The advent of the bromodeoxyuridine(BrdU)-differential staining techniques has greatly facilitated the detection of sister chromatid exchanges (SCE). These SCE have been demonstrated to be an accurate reflection of DNA damage both in vitro in cultured cells and in vivo in mouse and rate bone marrow and spleen cells. In this review, we examine the effect of cellular aging on both baseline and mutagen-induced SCE levels. In all systems examined, aging did not appear to significantly affect the baseline levels of SCE. However, in human fibroblast cultures we have found a significant decrease in the levels of mutagen-induced SCE as a function of both in vitro passage level (in vitro aging) and the age of the cell culture donor (in vivo aging). In addition we have found a similar decrease in mutagen-induced SCE levels in both mouse and rat bone marrow cells and mouse spleen cells where examinations were performed entirely in vivo. Diminished mutagen-induced SCE levels were obtained with a wide variety of agents including mitomycin-C, cyclophosphamide, adriamycin, ethyl methanesulfonate and N-acetyl-2-acetoxyamino-fluorene. These decreased SCE levels were accompanied by increased frequencies of chromosomal aberrations in the older cell populations. If SCE represents a form of DNA repair as has been suggested by several investigators, our finding would indicate impaired DNA repair occurring in old cells.

Aging↗
PubMed1978

Modulation of the acquisition and expression of immunity by Tilorone: I. Delayed-type hypersensitivity responses.

The chronic administration of Tilorone [(2,7-bis(diethylamino)ethoxy]fluoren-9-one) with antigen seems to prevent the generation of DTH effector cells. The administration of Tilorone proximal to DTH challenge blocks the expression of DTH. By local transfer of DTH effector cells, this latter effect can be shown to be due to the lack of nonspecific inflammatory cells. By the use of both systemic and local transfer systems, it is also shown that specific DTH effector cells from animals treated with Tilorone are unable to circulate in the normal manner. Overall, these experiments suggest that Tilorone does not block the generation of DTH effector cells, but it does greatly alter the expression of DTH. The relation between these effects and the known interferon induction capacity on Tilorone remains unclear.

Animals↗
PubMed1978

Modulation of the acquisition and expression of immunity by Tilorone: II. Humoral responsiveness.

Tilorone (2,7-bis[(diethylamino)ethoxy]fluoren-9-one) can enhance the humoral immune response of mice to SRBC although Tilorone has no effect on functional activity of splenic B cells in the absence of immunogen. Tilorone does not alter the effective level of T cell help but does seem to alter the level of effective suppression. Tilorone seems to be an adjuvant only in the sense of removing a normal homeostatic control mechanism, perhaps suppressor T cells.

Adjuvants, Immunologic↗
PubMed1977

The use of rec-bacteria for testing of carcinogenic substances.

A series of rec-Escherichia coli strains were tested for their sensitivity to four known carcinogenic compounds by examination of a zone of inhibited bacterial growth around a central well containing the test chemical. The mutants recA-, recB-, recC-, and recA- recB- recC- were all more sensitive to the mutagens than the parental strain AB1157. The recB- recC- strain was examined with a larger series of compounds and was found to respond to many of the substances in a similar way as the Salmonella typhimurium strains of Ames but with some notable exceptions. Nitrosamines, with rat liver microsomal activation, could be detected at lower levels and a group of aromatic amino compounds failed to react with these rec-E. coli. An unusual feature of these rec-mutants is their sensitivity to mixtures of nitrosamines and 2-acetyl amino-fluorene in the absence of microsomal activation.

2-Acetylaminofluorene↗
PubMedDate not supplied

Mutagenicity of polycyclic aromatic compounds (PAC) identified in source emissions and ambient air.

Several polycyclic aromatic compounds (PAC) including nitrated and oxygenated derivatives of polycyclic aromatic hydrocarbons (PAH) were tested for mutagenic activity in the Salmonella/microsome assay. Among the compounds tested the isomer mix of nitro-1-hydroxypyrenes showed the highest direct mutagenic response in both the Salmonella strain TA98 and TA100 (1251 revertants/micrograms and 463 revertants/micrograms, respectively). The direct-acting mutagenicity of the nitro-1-hydroxypyrene isomer mix was dependent upon reduction of the nitro function as evidenced by the decrease in activity observed with the nitroreductase-deficient and arylhydroxylamine esterifying-deficient tester strains. The oxygenated derivatives of PAH containing aldehyde or keto groups showed weak or no mutagenic responses. In most cases addition of S9 was essential for any mutagenic activity and the strain TA100 was more sensitive than the strain TA98. Within this group, 7H-dibenzo[c,g]fluoren-7-one showed the highest mutagenic effect; 7 and 22 revertants/micrograms using the strains TA98 and TA100, respectively.

Air Pollutants↗
PubMedDate not supplied

Ames Salmonella/mammalian-microsome testing of peptides and peptide synthesis reagents.

The Ames Salmonella/mammalian-microsome assay was used to evaluate the bacterial mutagenicity of 6 bioactive peptides and of 11 chemical reagents used in peptide synthesis. Samples of 2 reagents, bis(2-oxo-3-oxazolidinyl)phosphinic chloride and fluoren-9-ylmethyl chloroformate, showed mutagenic activity with strains TA100 and TA1535, and with TA1537, respectively. No mutagenic activity was found with the bioactive peptides or with the other 9 peptide synthesis reagents.

Animals↗
PubMed1991

Simultaneous analysis of chromosomal aneusomy and 5-bromodeoxyuridine incorporation in MCF-7 breast tumor cell line.

We describe a new method to determine simultaneously both proliferative status and chromosome copy number within individual interphase cells. The MCF-7 human breast cancer cell line was used as a model system to characterize proliferative activity in karyotypically defined cell subpopulations. Cells were labeled with bromodeoxyuridine (BrdU) in vitro and incorporation was monitored with IU4 mouse anti-BrdU. Biotinylated, digoxigenin-labeled, or acetylamino-fluorene-conjugated repetitive sequence DNA probes were hybridized to target interphase nuclei. Three-color fluorescence labeling allowed simultaneous detection of two chromosome pairs and designation of cells undergoing DNA synthesis. This technique may also be used for simultaneous characterization of proliferative and karyotypic heterogeneity in primary human tumors.

Aneuploidy↗
PubMed1983

A rapid and simple method to quantitate chemically induced unscheduled DNA synthesis in freshly isolated rat hepatocytes facilitated by DNA retention of membrane filters.

The filter elution method used for the detection of DNA strand breaks has been modified to quantitate chemically induced DNA repair which is measured as unscheduled DNA synthesis (UDS) in suspension of freshly isolated rat hepatocytes. Our method is based on DNA purification by retention on polyvinyl chloride filters, and is capable of handling a large number of samples simultaneously. By using the present assay system, positive dose-dependent UDS data was obtained on the following carcinogens: aflatoxin B1, 2-acetylaminofluorene, 4-aminobiphenyl, 2-aminofluorene, methyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, and 4-nitroquinoline-1-oxide. In contrast, non-carcinogenic biphenyl, fluorene, and sodium ascorbate did not elicit any detectable levels of UDS at all concentrations tested. Thus, UDS as measured by the present filter retention method may serve as an efficient and reliable means of screening chemical mutagens/carcinogens.

Animals↗