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At least 19 recordsLinked to original sources
PubMed1994

Biomonitoring of hemoglobin adducts: aromatic amines and tobacco-specific nitrosamines.

A new analytical procedure has been developed for the simultaneous determination of human hemoglobin adducts from aromatic amines and tobacco-specific nitrosamines. These tobacco-related hemoglobin adducts were determined in nonsmokers, smokers, and users of nasal snuff. Adducts from aminobiphenyl compounds are good biomarkers of exposure to tobacco smoke; they are not elevated in users of nasal snuff. However, a significant contribution of environmental exposure to aromatic amines and/or the corresponding nitroaromatics makes it difficult to evaluate passive exposure to tobacco smoke. The best biomarkers for exposure to tobacco smoke should in theory be adducts arising from tobacco-specific nitrosamines. The common adduct from N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone releases 4-hydroxy-1-(3-pyridyl)-1-butanone from hemoglobin upon mild alkaline hydrolysis and only marginal differences are found in the adduct level in smokers and nonsmokers. The reason for this observation is not yet understood and is currently under investigation. However, the adduct formed by tobacco-specific nitrosamines is well suited for the detection of oral and nasal tobacco use. Only by simultaneous determination of both adducts formed by aromatic amines and tobacco-specific nitrosamines is it possible to differentiate between nonsmokers, smokers, and nasal snuff users.

Aminobiphenyl Compounds↗
PubMed1985

The modulation by arylamines of the in vitro formation of superoxide anion radicals and hydrogen peroxide by rat liver microsomes.

A concentration-dependent increase in the generation of the superoxide anion radical (O-2), was observed during the incubation of benzidine (0.1-5 mM), but not of the structurally related compounds 4-aminobiphenyl, 2-aminobiphenyl or 4-fluoro-4'-aminobiphenyl, with NADPH-supplemented rat liver microsomes. This increase was partially inhibited by carbon monoxide and catalase but unaffected by 4-aminobiphenyl, a substrate of the cytochrome P-450 system. Microsomes from benzo(a)pyrene-treated, but not microsomes from phenobarbitone-pretreated rats, were responsible for a larger benzidine-dependent effect compared to microsomes from control animals. In contrast to the above observations, benzidine decreased the formation of hydrogen peroxide by NADPH-supplemented microsomal preparations from untreated rats. These results indicate that free radicals of oxygen are generated during the metabolism of some arylamines.

Amines↗
PubMed1985

Formation and persistence of arylamine DNA adducts in vivo.

Aromatic amines are urinary bladder carcinogens in man and induce tumors at a number of sites in experimental animals including the liver, mammary gland, intestine, and bladder. In this review, the particular pathways involved in the metabolic activation of aromatic amines are considered as well as the specific DNA adducts formed in target and nontarget tissue. Particular emphasis is placed on the following compounds: 1-naphthylamine, 2-naphthylamine, 4-aminobiphenyl, 4-acetylaminobiphenyl, 4-acetylamino-4'-fluorobiphenyl, 3,2'-dimethyl-4-aminobiphenyl, 2-acetylaminofluorene, benzidine, N-methyl-4-aminoazobenzene, 4-aminoazobenzene, and 2-acetylaminophenanthrene.

1-Naphthylamine↗
PubMed1990

Haemoglobin adducts formed by aromatic amines in smokers: sources of inter-individual variability.

In a previous study we found that aromatic amines, particularly 4-aminobiphenyl, formed haemoglobin adducts at higher concentrations in the blood of smokers compared to non-smokers. We re-analyse here data on haemoglobin adducts of 14 aromatic amines in order to ascertain if the inter-individual variability left unexplained by tobacco smoking could be attributed to differences in individual metabolic patterns. For this purpose we computed residuals from analysis of variance in order to adjust for individual smoking habits (type and amount of tobacco). Residuals were correlated within two clearly distinct groups: one formed by binuclear compounds (4-aminobiphenyl, 3-aminobiphenyl and 2-naphthylamine) and the other formed by all other (i.e. mononuclear) compounds. Within each group, highly statistically significant correlation coefficients were found, whereas compounds belonging to one group were not correlated to compounds in the other group. These results can be interpreted as a suggestion that two different metabolic pathways exist, one for binuclear and one for mononuclear arylamines, and that inter-individual differences in such pathways can explain part of inter-individual variability in adduct levels. This interpretation is consistent with recent animal experiments suggesting that there are different enzyme systems for the two classes of compounds.

2-Naphthylamine↗
PubMed1999

Base-substitution profiles of externally activated polycyclic aromatic hydrocarbons and aromatic amines determined in a lacZ reversion assay.

Using an improved set of lactose-auxotrophic Escherichia coli tester strains, the proportion of the six possible transitions and transversions after mutagen exposure was assessed. Mutagenic specificity was determined in plate-incorporation assays using lactose-containing minimal medium for the selection of revertants, either after application of directly acting mutagens or by including a metabolic activation system with rat liver S9-extract. The differential and dose-dependent response of the six tester strains was shown by treating the bacteria with described diagnostic mutagens and other directly DNA damaging substances, e.g., N-methyl-N-nitrosoguanidine (MNNG) and benzo[a]pyrene-diolepoxide (BPDE). Polycyclic aromatic hydrocarbons and aromatic amines were investigated in the presence of an external metabolic activation system. Benzo[a]pyrene (BaP) yielded similar mutation profiles as its ultimate mutagen BPDE, if 100-fold increased doses were applied. In contrast to the mutation profile of BaP, which was dominated by G:C-T:A transversions, mutagenesis with benzo[c]phenanthrene (BcPh) produced predominantly A:T-T:A transversions. The same base change was observed with 5-methylchrysene and found to be missing with 5,6-dimethylchrysene, while both compounds caused G:C-A:T transitions. The aromatic amines 4-aminobiphenyl (4-ABP), 2-aminoanthracene (2-AA) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) yielded similar yet distinguishable mutation profiles. Base-substitution reversion profiles of the chemical mutagens were in agreement with those obtained in other systems and with molecular analysis of mutants induced by these agents.

Amines↗
PubMed1994

Glucuronidation of carcinogenic arylamines and their N-hydroxy derivatives by rat and human phenol UDP-glucuronosyltransferase of the UGT1 gene complex.

Since carcinogenic arylamines are sequentially oxidized and conjugated with glucuronic acid, differences in glucuronidation may critically determine the toxic potential of these compounds. Therefore, N-glucuronidation of 1- and 2-naphthylamine (1-NA and 2-NA),4-aminobiphenyl(4-ABP) and their N-hydroxy derivatives was investigated using rat and human liver microsomes and V79 cell-expressed phenol UDP-glucuronosyltransferases (UGT) of the UGT1 gene complex. Cell-expressed UGTs included rat and human UGT1.6, which are known to conjugate planar phenols, and human UGT1.7, conjugating both planar and bulky phenol. (i) N-Glucuronidation of 1- and 2-NA and of N-hydroxy-2-NA was inducible by 3-methylcholanthrene in rat liver microsomes whereas N-glucuronidation of the bulky arylamines 4-ABP and N-hydroxy-4-ABP was not. In support of these findings mutagenicity of N-hydroxy-2-NA in the Ames test was markedly reduced upon addition of UDP-glucuronic acid using liver homogenates from 3-methylcholanthrene-treated rats. (ii) With cell-expressed rat UGT1.6, non-carcinogenic 1-NA was conjugated with the highest rate and with higher affinity than 2-NA. UGT1.6 showed poor activity towards N-hydroxy-4-ABP and 4-ABP. (iii) Substrate specificity of human UGT1.6 also appeared to be limited to planar 1-NA, 2-NA and its N-hydroxy derivative, whereas UGT1.7 showed broader substrate specificity, including the bulky arylamine 4-ABP and its N-hydroxy derivative. The results suggest marked differences in substrate specificity of different UGT isozymes for arylamines and their N-hyroxy derivatives.

1-Naphthylamine↗
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↗
PubMed1977

Failure of the N-oxodized metabolites of some carcinogenic amines to induce tumors in normal and wounded rat skin.

The skin of Osborne-Mendel and Sprague-Dawley rats was treated by repeated topical application of 1- and 2-naphthylamine, 4-biphenylamine and their corresponding N-arylhydroxylamine and nitroso derivatives for 52 weeks. In addition, the possibility of enhancing the susceptibility of the skin to the tumor induction by periodic wounding at the site of compound application was investigated in the Sprague-Dawley strain. The animals were observed for an additional year after which all survivors were sacrificed. No skin tumours were elicited in any of the rats although a small number of systemic tumors at sites distant from the area of application were observed in the Osborne-Mendel strain. No discernable increase in the sensitivity of the skin as a consequence of wounding to the carcinogenic effect of the compounds tested were observed.

1-Naphthylamine↗
PubMed2005

Effect of inhibitors of histone deacetylase on the induction of cell differentiation in murine and human erythroleukemia cell lines.

Histone deacetylase (HDAC) inhibitors are a novel class of promising anti-cancer agents. Little information is available on the capacity of structurally different HDAC inhibitors to induce terminal cell differentiation in different cell types in relation to enzyme inhibition and subtype selectivity. Consequently, the aim of this study was to provide a comprehensive comparison of these effects. New biarylalanine inhibitors of HDAC were synthesized and compared to a series of standard inhibitors from different laboratories. Chromatographically purified rat liver and immunoprecipitated FLAG-tagged recombinant human HDACs were used as sources of HDAC activity. Enzyme inhibition was studied using a fluorescent substrate and its conversion was monitored by high-performance liquid chromatography. The ability to induce cell differentiation was compared in murine (Friend DS-19) and human (K562) erythroleukemic cell lines, and was quantified by benzidine staining. Inhibition of cell proliferation was evaluated by cell counting. All HDAC inhibitors were identified as potent inhibitors of erythroleukemic cell proliferation. However, we observed a complex pattern of differentiation induction: structurally similar inhibitors resulted in disparate activity profiles, whereas similar profiles were detected within distinct structural classes. Among the newly synthesized biarylalanine compounds, a 3'-methoxy derivative was identified as a very effective inducer of terminal cell differentiation. We conclude that investigation of subtype selectivity of selected HDAC inhibitors does not provide a clear link between selectivity and the observed cellular activity profile. The predictive value of in vitro HDAC inhibition assays for identifying anti-proliferative compounds has been emphasized.

Aminobiphenyl Compounds↗
PubMed1981

Metabolic activation of aromatic amines and azo dyes.

Aromatic amines, amides and nitro compounds are a class of chemicals that produce tumors in a wide variety of tissues in experimental animals, including liver, urinary bladder, forestomach, small intestine, Zymbal's gland, subcutaneous tissue or skin. In man, exposure to some aromatic amines is associated with tumours of the urinary bladder and carcinoma of the renal pelvis. Their biological activity as carcinogens or genotoxic agents is, in all the cases that have been studied in detail, dependent on metabolic activation in vivo, occurring by multiple pathways. Differences in these metabolic pathways may largely account for the differences in tissues and species susceptibilities to cancer induction. Carcinogenicity of aromatic amines or amides is dependent on their oxidation to N-hydroxy derivatives, whilst the carcinogenicity of aromatic nitro compounds is linked to their reduction to hydroxylamines. Further conversion of the N-hydroxylamine or N-hydroxyamide to reactive intermediates can occur in several ways, which include (i) esterification of the N-hydroxy group, (ii) non-enzymic protonation of the nitrogen of the hydroxylamine and (iii) oxidation to a free radical of arylhydroxamic acids. Following generation of such reactive electrophilic intermediates in tissues or cells, macromolecular binding has been observed to nucleic acids and proteins. In many cases, arylamidated and arylaminated products are formed with nucleic acid bases; in the case of the well-studied 2-acetylaminofluorene, nucleophilic atoms of guanine are the predominant site of reaction. Relatively little is known of the structure and biological consequences of DNA adducts formed from other aromatic amines, amides or nitro compounds; more research in these directions is warranted.

1-Naphthylamine↗
PubMed1997

Base-pair mutation caused by four nitro-group containing aromatic amines in Salmonella typhimurium TA100, TA104, TA4001 and TA4006.

Among p-phenylenediamine, benzidine and the analogues we previously tested, only the nitro-group containing 2-nitro-p-phenylenediamine, 3-nitro-o-phenylenediamine, 4-nitro-o-phenylenediamine and 4,4'-dinitro-2-biphenylamine caused base-pair reversion in the histidine locus of Salmonella typhimurium TA100. In order to determine the types of mutations involved, such as transversion or transition, these four nitro-group containing compounds were tested with S. typhimurium strains TA100, TA104, TA4001 and TA4006. Dose-mutagenicity relationships occurred with TA100 and TA104. However, the majority of revertants from TA100 and TA104 were insensitive to inhibition by histidine analogue, DL-1,2,4-triazole-3-alanine. These results suggested that the occurrence of histidine revertants was predominantly induced by base-pair (point) mutations and not by suppressor gene mutations. The CG-TA transition and CG-AT transversion are the major types of mutation induced by all these compounds in TA100. The TA-AT transversion also contributed to the mutagenicity of 4-nitro-o-phenylenediamine and 4,4'-dinitro-2-biphenylamine in TA104. These nitro-group containing compounds showed no mutagenicity in TA4001, but induced CG-GC transversion in TA4006.

Aminobiphenyl Compounds↗
PubMed1996

Antimutagenicity of yogurt.

Yogurt is milk fermented by a mixture of two bacteria: Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus salivarius ssp. thermophilus. Epidemiological studies have correlated a reduced risk of colon cancer with yogurt consumption. Independent studies have established that yogurt and extracts thereof are antimutagenic. Although multiple explanations can account for yogurt's putative anticarcinogenicity, we are interested in testing the hypothesis that antimutagenic compounds produced during fermentation are responsible. We recently reported on the antimutagenicity of an acetone extract of yogurt against the experimental carcinogens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 3.2'dimethyl-4-aminobiphenyl (DMAB) (Mutation Res. (1995) 334, 213-224). We are now aware that palmitic acid is an active ingredient against MNNG.

Aminobiphenyl Compounds↗
PubMed1996

G-actin as a risk factor and modulatable endpoint for cancer chemoprevention trials.

Because tumorigenesis is an ongoing process, biomarkers can be used to identify individuals at risk for bladder cancer, and treatment of those at risk to prevent or slow further progression could be an effective means of cancer control given accurate individual risk assessment. Tumorigenesis proceeds through a series of defined phenotypic changes, including those in genetically altered cells destined to become cancer as well as in surrounding normal cells responding to the altered cytokine environment. A panel of biomarkers for the changes can provide a useful system for individual risk assessment in cancer patients and in individuals exposed to carcinogens. The use of such markers can increase the specificity of chemoprevention trials by targeting therapy to patients likely to respond, and thereby markedly reduce the costs of the trials. Previous studies in our laboratories showed the cytoskeletal proteins G- and F-actin reflect differentiation-related changes in cells undergoing tumorigenesis and in adjacent "field" cells, and a pattern of low F-actin and high G-actin is indicative of increased risk. Actin changes may be a common feature in genetic and epigenetic carcinogenic mechanisms. In a group of over 1600 workers exposed to benzidine, G-actin correlated with exposure, establishing it as an early marker of effect. In another study, a profile of biomarkers was monitored in patients who underwent transurethral resection of bladder tumor (TURBT) and received Bacillus Calmette Guerin (BCG) and/or DMSO. The primary objective was to determine how the defined biomarkers expressed in the tumor and the field correlate with clinical response and recurrence. DMSO, known to modulate G-actin in vitro, was used as an agent. Results strongly support the hypothesis that cytosolic G-actin levels measured by quantitative fluorescence image analysis (QFIA) can be an important intermediate endpoint marker for chemoprevention and that the p300 (M344) and DNA ploidy markers identify a high-risk group that requires more aggressive therapy and recurrence monitoring. Further research with other markers has shown that DD23 and nuclear actin, both of which identify late, specific changes, may increase the battery of useful markers. Taken together these studies show how biomarkers are employed to study individuals at risk, aid in the selection of chemopreventive compounds and assist in the understanding of the pathogenesis of malignancy.

Actins↗
PubMedDate not supplied

[Some properties of aromatic amines].

The human carcinogenic activity of 4-4' amino diphenyl and 2 amino naphthalene, drew occupational physician's attention to "aromatic amines" as potentially carcinogenic compounds. The chemical-physical and biological properties of groups of products with structure very similar to them, show that the expression "aromatic amines" cannot define a class of compounds, but that it is necessary to consider only individual substances. The solutions carried out in industry for the replacement of some human cancerogenic products are reported.

1-Naphthylamine↗
PubMed1992

A quantitative assessment of the cytotoxicity associated with chromosomal aberration detection in Chinese hamster ovary cells.

Regulatory guidelines suggest testing chemicals up to cytotoxic doses in chromosomal-aberration assays. To investigate the utility and limitations of various cytotoxicity indicators we used Chinese hamster ovary (CHO) cells to test 8 chemicals with differing ratios of cytotoxicity to clastogenicity. We measured immediate or delayed cell killing and growth inhibition (ATP levels, cell counts, colony-forming efficiency, CFE) and cell-cycle perturbations (mitotic index, MI; average generation time, AGT). Aberrations (abs) were scored 10 and 24 h from the beginning of the 3-h treatment. All 8 compounds induced abs at concentrations that reduced cell growth at 24 h by 50% or less. Concentrations of each chemical which induced at least 15% cells with abs, gave little loss of CFE (0-20%) for mitomycin C, adriamycin, cadmium sulfate and 2,6-diaminotoluene in contrast to the marked loss of CFE (70-80%) for eugenol (EUG), 2-aminobiphenyl and 8-hydroxyquinoline (8-HQ). 2,4-Diaminotoluene (2,4-DAT) was intermediate. Higher aberration yields were found at 24 h than at 10 h, even when minimal cell-cycle delay was detected by AGT estimates from BrdUrd-labeled cells. Cells with multiple abs were seen at 24 but not at 10 h, and often confirmed clastogenicity when there was only a weak increase in the percentage of cells with aberrations. Total ATP per culture did not always correlate with cell number, especially at later times after treatment. This is likely due to metabolic perturbations or altered cell biomass that are known to affect cell ATP content. MI suppression often did not correlate with AGT, e.g., only small increases in AGT were seen for 8-HQ, 2,4-DAT and EUG despite severe mitotic suppression at 10 h. By 24 h the MI for all chemicals had recovered, sometimes exceeding control levels. Marked mitotic accumulation was seen at 10 h for 2,4-DAT, indicating cell synchrony. Thus, the MI has limited value for dose selection. In conclusion, even weakly active chemicals were detected at a single time without exceeding a 50% growth reduction at 24 h.

Aminobiphenyl Compounds↗
PubMed1992

Effect of sampling time on chromosome aberration yield for 7 chemicals in Chinese hamster ovary cells.

Choice of harvest time is one of the most important variables in the assessment of whether a compound is clastogenic and in establishing a dose relation. We examined the effects of sampling time on aberration yield for 7 diverse chemicals in CHO-WBL cells by harvesting at intervals from 9 to 30 h after treatment for 3 h with or without S9 metabolic activation. We observed both the percentage of aberrant cells and the total number of aberrations. Our data suggest that for most compounds a single harvest time approximately 17-21 h after the beginning of a 3-h treatment is optimal for aberration detection in CHO cells. Maximal aberration yields were observed for 2,4-diaminotoluene, 2,6-diaminotoluene and cytosine beta-D-arabinofuranoside from 17 to 21 h, eugenol from 15 to 21 h, cadmium sulfate from 15 to 24 h and 2-aminobiphenyl, from 17 to 24 h. For adriamycin at 1 microM, the % aberrant cells remained elevated throughout the period from 9 to 29 h, while small increases at 0.1 microM ADR were found only at 13 and at 25 h. For most chemicals the maximal aberration yield occurred at a different time for each concentration tested. However, the use of 3 or more closely spaced concentrations, carefully selected to yield up to 50% toxicity, allowed detection of a positive response at a single harvest time for all 7 chemicals.

Aminobiphenyl Compounds↗