RESUMO
In this Letter, we illustrate how polarized neutron scattering can be used to isolate the spin-spin correlations of modes forming flat bands in a frustrated magnetic system hosting a classical spin liquid phase. In particular, we explain why the nearest-neighbor spin ice model, whose interaction matrix has two flat bands, produces a dispersionless (i.e., "flat") response in the non-spin-flip (NSF) polarized neutron scattering channel and demonstrate that NSF scattering is a highly sensitive probe of correlations induced by weak perturbations that lift the flat band degeneracy. We use this to explain the experimentally measured dispersive (i.e., nonflat) NSF channel of the dipolar spin ice compound Ho_{2}Ti_{2}O_{7}.
RESUMO
The role of the rotavirus non-structural proteins NSP1 and NSP3 in regulating cellular and viral mRNA translation has been investigated by examining the effect of added recombinant NSP3 on protein translation in a T7-based in vitro coupled transcription-translation system. Addition of purified NSP3 to assays primed solely with cellular mRNA was found to have no effect on the translation efficiency of the mRNA. However, as expected, the addition of viral mRNA to such assays competitively inhibited the synthesis of cellular protein, and interestingly, this inhibition was enhanced by the addition of NSP3. Treatment of NSP3 with antisera raised against the purified protein abrogated its function, but only when used prior to mixing the protein with viral mRNA. Addition of partially purified NSP1 to the coupled system was able to alleviate the enhancement of the inhibition of cellular mRNA translation caused by NSP3. The role of NSP1 in this process appears to be to modulate the impact of the NSP3-based inhibition of cellular translation by binding to the 5' end of viral mRNAs.
Assuntos
Genes Virais , Rotavirus/genética , Proteínas não Estruturais Virais/genética , Sequência de Bases , Primers do DNA/genética , Regulação Viral da Expressão Gênica , Humanos , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Rotavirus/fisiologia , Proteínas não Estruturais Virais/metabolismo , Replicação ViralRESUMO
Cocaine administration upregulates the levels of extracellular glutamate and dopamine in the striatum. Activation of the receptors alters calcium homeostasis in striatal neurons leading to the expression of the endoplasmic reticulum (ER) stress proteins. It was therefore hypothesized that cocaine upregulates the expression of the ER stress proteins, immunoglobulin heavy chain binding protein (BiP), Ire1alpha and perk via glutamate and dopamine receptor activation. A novel glutamate microbiosensor and Western immunoblot analyses were mainly performed to test the hypothesis in the rat dorsal striatum. The results showed that i.p. injection of repeated cocaine (20 mg/kg) for nine consecutive days significantly increased extracellular glutamate levels while acute cocaine injection did not. However, the immunoreactivities (IR) of the ER stress proteins in the dorsal striatum were significantly increased by either acute or repeated cocaine injections as compared with saline controls. Intrastriatal injection (i.s.) of the selective group I metabotropic glutamate receptor (mGluR) antagonist N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC; 25 nmol) or the mGluR5 subtype antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP; 2 and 25 nmol) significantly decreased repeated cocaine-induced increases in the IR of the ER stress proteins in the injected dorsal striatum. Similarly, the selective D1 antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 mg/kg, i.p.) or the N-methyl-d-aspartate antagonist dizocilpine/(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-ibenzo[a,d]cyclohepten-5,10-imine maleate (MK801; 2 nmol, i.s.) decreased acute or repeated cocaine-induced the IR of the ER stress proteins in the dorsal striatum. These data suggest that cocaine upregulates expression of the ER stress proteins in striatal neurons via a mechanism involving activation of glutamate and dopamine receptors.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Neurônios/metabolismo , Estresse Fisiológico/induzido quimicamente , Animais , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Corpo Estriado/metabolismo , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Retículo Endoplasmático/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteínas de Choque Térmico/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Masculino , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/efeitos dos fármacos , Chaperonas Moleculares/metabolismo , Neurônios/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Fisiológico/metabolismo , Estresse Fisiológico/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , eIF-2 Quinase/efeitos dos fármacos , eIF-2 Quinase/metabolismoRESUMO
The catabolism of tryptophan by rat intestinal microflora was studied for the production of mutagenic metabolites that might be involved in the etiology of colon cancer. Various tryptophan metabolites were assayed for mutagenic and comutagenic activity in the Ames bacterial test system. These included metabolites that were identified by thin-layer chromatography in cultures of rat fecal bacteria, other compounds structurally related to tryptophan, whole unfractionated mixed fecal bacteria culture filtrates, and concentrated solvent extracts. A total of 27 materials were tested with 5 Salmonella strains in the mutagenesis assay. Most substances were inactive, and only one compound, o-aminoacetophenone, which was unlikely to be produced in the intestine, showed weak comutagenic activity. Our results did not support the hypothesis that tryptophan metabolites produced by intestinal microflora are major etiologic factors in cancer of the colon.
Assuntos
Intestinos/microbiologia , Mutagênicos , Triptofano/metabolismo , Acetofenonas/farmacologia , Animais , Carcinógenos , Dieta , Sinergismo Farmacológico , Fezes/microbiologia , Ácidos Indolacéticos/metabolismo , Indóis/metabolismo , Mucosa Intestinal/metabolismo , Neoplasias Intestinais/etiologia , Carne , Ratos , Salmonella typhimurium/efeitos dos fármacos , Triptofano/toxicidadeRESUMO
Twenty-three strains of intestinal anaerobes obtained from two laboratories were examined for indole production from tryptophan. Among the 23 isolates tested, three of Bacteroides fragilis thetaiotaomicron and one Citrobacter sp. were indole positive. The tryptophanase of the indole-positive strains of intestinal anaerobes was inducible by tryptophan and was susceptible to glucose repression. The products of tryptophanase activity were formed in stoichiometric amounts by dialyzed, freshly prepared extracts. The tryptophan concentration and tryptophanase activity in feces from rats on an all-meat diet were significantly higher than those in feces from rats on a normal diet. The results indicated that the higher tryptophanase activity in the feces of rats fed an all-meat diet is due to the inducibility of this enzyme by tryptophan and is not due to any inhibitor in the feces of rats on a normal diet. The results also suggested that a population with a diet rich in meat has a greater chance for exposure to possible carcinogens such as indole and other tryptophan metabolites. This agrees with the hypothesis, based on epidemiologic data, that a high intake of meat may be related to the development of colon cancer in man.
Assuntos
Citrobacter/enzimologia , Neoplasias do Colo/enzimologia , Escherichia/enzimologia , Fezes/enzimologia , Intestinos/microbiologia , Liases/metabolismo , Triptofanase/metabolismo , Bacteroides/enzimologia , Bacteroides/isolamento & purificação , Citrobacter/isolamento & purificação , Neoplasias do Colo/etiologia , Neoplasias do Colo/microbiologia , Dieta , Indução Enzimática , Repressão Enzimática , Fezes/metabolismo , Glucose/farmacologia , Humanos , Indóis/metabolismo , Piruvatos/metabolismo , Triptofano/metabolismoRESUMO
To identify cytotoxic T-cell (CTL) epitopes against human papillomavirus type 18 (HPV 18) E6 protein that might be useful for developing peptide-based vaccine against HPV 18 infection, 18 peptides which possibly contain CTL epitopes were selected on the basis of previously described human leukocyte antigen (HLA)-A2.1-binding motif and chemically synthesized. In the binding assay of the synthetic peptides, 8 out of 18 synthetic peptides enhanced the expression of HLA-A2.1 molecules on T2 cell surface, which implies that these peptides were able to bind the HLA molecules. Those peptides having good binding affinity to HLA-A2.1 were tested for their ability to activate CTLs which were isolated from peripheral blood mononuclear cells (PBMCs) of healthy blood donors and to kill the target T2 cells pulsed with the same peptide. Five out of eight tested peptides activated CTLs and killed the target cells.
Assuntos
Proteínas de Ligação a DNA , Antígeno HLA-A2/imunologia , Proteínas Oncogênicas Virais/imunologia , Papillomaviridae/imunologia , Linfócitos T Citotóxicos/imunologia , Sítios de Ligação , Linhagem Celular , Células Cultivadas , Humanos , Leucócitos Mononucleares/imunologia , Proteínas Oncogênicas Virais/síntese química , Peptídeos/síntese química , Peptídeos/imunologiaRESUMO
The Ames Salmonella/microsome assay was employed to test the mutagenicity of benzidine and its analogs using strains TA98 and TA100 in the presence and absence of Aroclor 1254-induced rat S9 mix. 3,3'-Dichlorobenzidine-2HCl and 4,4'-dinitro-2-biphenylamine were directly mutagenic to TA98, while 4,4'-dinitro-2-biphenylamine was directly mutagenic to both TA98 and TA100 in the absence of S9 mix. 2-Aminobiphenyl, 3-aminobiphenyl, and 3,3'-5,5'-tetramethylbenzidine were not mutagenic in either strains in the presence or absence of S9. In the presence of S9 mix, 4-aminobiphenyl, benzidine, 3, 3'-dichlorobenzidine-2HCl, 3,3'-dimethoxybenzidine, 3,3'-4, 4'-tetraaminobiphenyl, o-tolidine, N, N-N', N'-tetramethylbenzidine, and 4,4'-dinitro-2-biphenylamine were mutagenic to TA98; 4-aminobiphenyl, 3,3'-dichlorobenzidine-2HCl, 3, 3'-dimethoxybenzidine, and 4,4'-dinitro-2-biphenylamine were mutagenic to TA100. Physicochemical parameters of these compounds including oxidation potentials, the energy difference between the lowest unoccupied molecular orbital and the highest occupied molecular orbital, ionization potentials, dipole moment, relative partition coefficient, and basicity did not correlate with their bacterial mutagenic activities.
Assuntos
Benzidinas/toxicidade , Mutagênicos/toxicidade , Animais , Testes de Mutagenicidade , Oxirredução , Ratos , Relação Estrutura-AtividadeRESUMO
The Ames Salmonella/microsomal assay was employed to test the mutagenicity of some benzamines (aniline, and o- and p-phenylenediamine) and their nitro-derivatives (p-nitroaniline, 2-nitro-p-phenylenediamine, 3- and 4-nitro-o-phenylenediamine), using strains TA98 and TA100 and their nitroreductase-deficient mutants, TA98NR and TA100NR, in the presence and absence of rat S9 mix. The addition of the nitro-group to benzamine molecules converted them into direct mutagens. Furthermore, the position of the nitro-group affected their mutagenic activities. Cytotoxicity testing with Chinese hamster ovary cells (CHO-K1) showed that the presence of the nitro-group in these compounds had no specific effect on toxicity. The test compounds all showed a dose-related increase in inducing chromosomal aberrations in CHO cells. However, the presence of the nitro-group did not affect potency in inducing chromosomal aberrations. Compounds containing the nitro-group had higher initial oxidation potentials and dipole moments (mu) than their nonnitro-containing counterparts. The mutagenicity and toxicity of these compounds were not related to physico-chemical properties, including oxidation potential, energy difference (deltaE) between the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO), ionization potential (I.P.), and mu.
Assuntos
Compostos de Anilina/toxicidade , Nitrocompostos/toxicidade , Compostos de Anilina/química , Animais , Biotransformação , Células CHO/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Aberrações Cromossômicas , Cricetinae , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Testes de Mutagenicidade , Nitrocompostos/química , Nitrorredutases/deficiência , Nitrorredutases/metabolismo , Oxirredução , Fenilenodiaminas/química , Fenilenodiaminas/toxicidade , Ratos , Ratos Sprague-Dawley , Salmonella typhimurium/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Kojic acid, a fungal metabolite produced by some species of Aspergillus and Penicillium, was found to induce sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of the rat liver S9 mix. Furthermore, this compound was demonstrated to induce mutations in Salmonella typhimurium strains TA98 and TA100 using both plate-incorporation and preincubation methods.
Assuntos
Pironas/toxicidade , Troca de Cromátide Irmã/efeitos dos fármacos , Animais , Células Cultivadas , Aberrações Cromossômicas , Cricetinae , Cricetulus , Feminino , Fígado/efeitos dos fármacos , Testes de Mutagenicidade , Ovário/efeitos dos fármacos , Ratos , Salmonella typhimurium/efeitos dos fármacosRESUMO
Dietary restriction (DR) reduced the metabolic activation of aflatoxin B1 (AFB1) in rats. This reduction may be attributed to the decrease of cytochrome P-450-mediated AFB1 epoxidation and/or increase in the detoxification of AFB1 catalyzed by hepatic glutathione S-transferase (GST) and other phase II detoxification enzymes. In this study the effect of DR on male rat liver cytosolic GST activity toward AFB1-8,9-epoxide was studied. The chemically-synthesized AFB1-8,9-epoxide was used as the substrate in this assay, and the formation of AFB1-GSH conjugate was analyzed by HPLC. Male Fischer 344 rats fed DR diets (60% of the food consumption of ad libitum (AL)-fed rats) showed a 2.4-fold increase in GST activity when AFB1-epoxide was used as the substrate. The results from the enzyme kinetic study showed that DR increased Vmax of the liver cytosolic GST but not the Km. Acute DR has little or no impact on GST activity when 1-chloro-2,4-dinitrobenzene and 2,4-dichloronitrobenzene were used as substrates. The mouse liver GST activity toward AFB1-epoxide was 3-fold greater than that of phenobarbital-induced rats, 4.5-fold greater than DR rats, and 14.7-fold greater than the GST activity of AL rats. This direct assay of liver GST activity using AFB1-epoxide as the substrate is useful for studying AFB1-induced biomarkers, such as AFB1-GSH conjugation and AFB1-DNA adducts.
Assuntos
Aflatoxina B1/análogos & derivados , Privação de Alimentos/fisiologia , Glutationa Transferase/metabolismo , Aflatoxina B1/metabolismo , Aflatoxina B1/toxicidade , Animais , Biotransformação/efeitos dos fármacos , Catálise , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/metabolismo , Citosol/efeitos dos fármacos , Citosol/enzimologia , DNA/efeitos dos fármacos , DNA/metabolismo , Adutos de DNA , Relação Dose-Resposta a Droga , Técnicas In Vitro , Fígado/efeitos dos fármacos , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Endogâmicos F344 , Especificidade por SubstratoRESUMO
Dietary restriction (DR) alters the activities of hepatic drug metabolizing enzymes and modulates the formation of carcinogen-DNA adducts in carcinogen treated animals. Our previous results showed that a 40% restriction of diet (60% of ad libitum (AL) food consumption) reduced the hepatic metabolic activation of aflatoxin B1 (AFB1) but increased the activation of benzo[a]-pyrene (BaP) in both rats and mice. In this study, the focus was directed toward the levels of carcinogen-DNA adducts formation and the carcinogen-induced DNA strand breaks in mouse kidney and liver DNA. DR significantly inhibited both AFB1-DNA adduct formation and AFB1-induced DNA strand breaks in kidney DNA of mice that received a single dose of [3H]AFB1 (5 mg/kg). The levels of AFB1-DNA adduct formation in mouse kidney DNA correlated well with increased AFB1-induced DNA strand breaks. The correlation between the levels of AFB1-DNA-adducts formed and DNA strand breaks in kidney DNA of DR-mice was less linear than between its AL-counterpart suggesting that other factors, such as different rates of DNA repair, may be involved. In addition, DR enhanced hepatic BaP- and 6-nitrochrysene (6-NC)-DNA adduct formation in the mice treated with BaP and 6-NC, respectively. The formation of the specific BaP-adduct, 10-(N2-deoxyguanosinyl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-BaP (N2-dG-BaP), in mouse liver was proportional to the dose, and was compatible to the BaP-induced DNA strand breaks affected by DR. The enhancement of the total 6-NC-DNA adduct formation in DR-mouse was also in correlation with the increased 6-NC-induced DNA strand breaks. The activity of mouse liver microsomal nitro-reductase increased by 2-fold in response to DR indicating that the nitroreduction may contribute to the increase of the metabolic activation of 6-NC. Our present results indicate that the effect of DR on the carcinogen activation is dependent upon the DR-modulated carcinogen metabolizing enzyme activities.
Assuntos
Aflatoxina B1/metabolismo , Carcinógenos/metabolismo , Adutos de DNA/metabolismo , Dano ao DNA , Privação de Alimentos/fisiologia , Aflatoxina B1/toxicidade , Animais , Benzo(a)pireno/metabolismo , Benzo(a)pireno/toxicidade , Biotransformação , Carcinógenos/toxicidade , Crisenos/metabolismo , Crisenos/toxicidade , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/enzimologia , Mutagênicos/metabolismo , Mutagênicos/toxicidade , Nitrorredutases/metabolismo , RatosRESUMO
The mutagenicity of p-phenylenediamine and its derivatives was tested using Ames Salmonella strains TA98 and TA100. p-Phenylenediamine was weakly mutagenic to TA98 with metabolic activation. 2-Nitro-p-phenylenediamine was directly mutagenic to both strains, while 2-methyl-p-phenylenediamine required S9 mix. All the test compounds induced a dose-related increase in chromosomal aberrations in Chinese hamster ovary (CHO) cells in the absence of the S9 mix. The mutagenicity and toxicity of these compounds did not correlate with their oxidation potentials, or any other tested physicochemical properties including the energy difference between the lowest unoccupied and the highest occupied molecular orbital, ionization potential, and dipole moment.
Assuntos
Carcinógenos/toxicidade , Corantes/toxicidade , Fenilenodiaminas/toxicidade , Animais , Biotransformação , Células CHO/efeitos dos fármacos , Aberrações Cromossômicas/genética , Corantes/metabolismo , Cricetinae , Relação Dose-Resposta a Droga , Testes de Mutagenicidade , Fenilenodiaminas/metabolismo , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Relação Estrutura-AtividadeRESUMO
Bacillus subtilis, Escherichia coli, Proteus vulgaris, Pseudomonas fluorescens, Salmonella sp. and Staphylococcus aureus were used to test the antimicrobial activity of tea flush extract and extracts of various tea products. Among the six test organisms, P. fluorescens was the most sensitive to the extracts, while B. subtilis was the least sensitive. In general, antimicrobial activity decreased when the extents of tea fermentation increased. The antimicrobial activities of tea flush extract and extracts of tea products with different extents of fermentation varied with test organisms. Tea flush and Green tea, the unfermented tea, exerted the strongest antimicrobial activity followed by the partially fermented tea products such as Longjing, Tieh-Kuan-Ying, Paochung, and Oolong teas. On the other hand, Black tea, the completely fermented tea, showed the least antimicrobial activity. It was also noted that extracts of Oolong tea prepared in summer exhibited the strongest antimicrobial activity, followed by those prepared in spring, winter and fall.
Assuntos
Antibacterianos/farmacologia , Fermentação , Extratos Vegetais/farmacologia , Chá , Bacillus subtilis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Proteus vulgaris/efeitos dos fármacos , Pseudomonas fluorescens/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Estações do Ano , Staphylococcus aureus/efeitos dos fármacosRESUMO
Azo dyes are widely used in textile, printing, cosmetic, drug and food-processing industries. They are also used extensively in laboratories as either biological stains or pH indicators. The extent of such use is related to the degree of industrialization. Since intestinal cancer is more common in highly industrialized countries, a possible connection may exist between the increase in the number of cancer cases and the use of azo dyes. Azo dyes can be reduced to aromatic amines by the intestinal microflora. The mutagenicity of a number of azo dyes is reviewed in this paper. They include Trypan Blue, Ponceau 3R, Pinceau 2R, Methyl Red, Methyl Yellow, Methyl Orange, Lithol Red, Orange I, Orange II, 4-Phenylazo-Naphthylamine, Sudan I, Sudan IV, Acid Alizarin Violet N, Fast Garnet GBC, Allura Red, Ponceau SX, Sunset Yellow, Tartrazine, Citrus Red No. 2, Orange B, Yellow AB, Carmoisine, Mercury Orange, Ponceau S, Versatint Blue, Phenylazophenol, Evan's Blue and their degraded aromatic amines. The significance of azo reduction in the mutagenesis and carcinogenesis of azo dyes is discussed.
Assuntos
Compostos Azo/metabolismo , Carcinógenos Ambientais , Animais , Compostos Azo/toxicidade , Biotransformação , Fenômenos Químicos , Química , Humanos , Neoplasias Intestinais/induzido quimicamente , Intestinos/microbiologia , MutagênicosRESUMO
Azo dyes are extensively used in textile, printing, leather, paper making, drug and food industries. Following oral exposure, azo dyes are metabolized to aromatic amines by intestinal microflora or liver azoreductases. Aromatic amines are further metabolized to genotoxic compounds by mammalian microsomal enzymes. Many of these aromatic amines are mutagenic in the Ames Salmonella/microsomal assay system. The chemical structure of many mutagenic azo dyes was reviewed, and we found that the biologically active dyes are mainly limited to those compounds containing p-phenylenediamine and benzidine moieties. It was found that for the phenylenediamine moiety, methylation or substitution of a nitro group for an amino group does not decrease mutagenicity. However, sulfonation, carboxylation, deamination, or substitution of an ethyl alcohol or an acetyl group for the hydrogen in the amino groups leads to a decrease in the mutagenic activity. For the benzidine moiety, methylation, methoxylation, halogenation or substitution of an acetyl group for hydrogen in the amino group does not affect mutagenicity, but complexation with copper ions diminishes mutagenicity. The mutagenicity of benzidine or its derivatives is also decreased when in the form of a hydrochloride salt with only one exception. Mutagenicity of azo dyes can, therefore, be predicted by these structure-activity relationships.
Assuntos
Compostos Azo/toxicidade , Corantes/toxicidade , Mutagênicos , Compostos de Anilina/química , Compostos de Anilina/toxicidade , Animais , Compostos Azo/química , Benzidinas/química , Benzidinas/toxicidade , Química Orgânica , Corantes/química , Desaminação , Humanos , Metilação , Nitrocompostos/química , Nitrocompostos/toxicidade , Fenômenos de Química Orgânica , Fenilenodiaminas/química , Fenilenodiaminas/toxicidade , Relação Estrutura-AtividadeRESUMO
The effect of caloric restriction (CR) on xenobiotic metabolizing enzyme activities results in alterations in the metabolic activation of chemical carcinogens, with a resultant impact on DNA-carcinogen adduct formation and DNA repair. Using aflatoxin B1 (AFB1) and benzo[a]pyrene (BP) as model carcinogens, we studied the effect of CR on the metabolic activation of these carcinogens and carcinogen-induced DNA damage and repair in terms of AFB1-DNA and BP-DNA adduct formation and removal. Male Fischer 344 rats fed calorie restricted diets (60% of the food consumption for ad libitum-fed rats) showed a reduction in the metabolic activation of AFB1 and decrease in both the in vitro and in vivo AFB1-DNA adduct formation. However, CR increased the activity of BP metabolizing enzymes resulting in an enhancement of BP-DNA adduct formation. Our results indicate that the effect of CR on metabolic activation of xenobiotics is dependent upon the selected xenobiotic metabolizing enzymes whose activities may be significantly altered by CR, and upon the nature of the chemical carcinogens which exert different structure-activity relationships during the process of chemically induced carcinogenesis.
Assuntos
Aflatoxina B1/farmacocinética , Benzo(a)pireno/farmacocinética , Carcinógenos/farmacocinética , Ingestão de Energia , Xenobióticos/farmacocinética , Animais , Biotransformação , Células Cultivadas , Dano ao DNA , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
Monocyclic aromatic amines (MAAs) are environmental pollutants. Many of them are genotoxic and impose hazards to human health. The mutagenicity of more than 80 of these amines was reviewed with primary emphasis on evaluation by the Ames Salmonella/microsome testing system. Many amines are mutagenic in Salmonella tester strains TA98 and TA100, but S9 mix is required for activity for most of the active ones. 2,4-Diaminotoluene, 2,4-diaminoethylbenzene, and a few amines containing a nitro-group are direct mutagens. There are several quantitative structure-activity relationship (QSAR) models which rationalize mutagenicity of many aromatic amines and several parameters, such as the lowest unoccupied molecular orbital energy (ELUMO), highest occupied molecular orbital energy (EHOMO), and hydrophobicity that are important. What factors determine the minimum requirement for the compound to be mutagenic and what factors determine the extent of mutagenicity suggest questions for further study.
Assuntos
Aminas/química , Aminas/farmacologia , Mutagênicos/química , Mutagênicos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Testes de Mutagenicidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Compostos de Aminobifenil/toxicidade , Mutação , Nitrocompostos/toxicidade , Fenilenodiaminas/toxicidade , Salmonella typhimurium/genética , Compostos de Aminobifenil/química , Composição de Bases , Relação Dose-Resposta a Droga , Genes Supressores , Testes de Mutagenicidade , Mutagênicos/química , Mutagênicos/toxicidade , Nitrocompostos/química , Fenilenodiaminas/química , Aldeído Pirúvico/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
2-Aminobiphenyl (2-ABP), 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP), but not benzidine (Bz) and biphenyl (Bp), were found to be inhibitory to the growth of human intestinal bacteria Bifidobacterium infantis ATCC 15697, B. bifidium ATCC 11863, Clostridium perfringens ATCC 13124, Escherichia coli ATCC 25922, E. coli ATCC 35218, Enterobacter cloacae ATCC 13047 and Salmonella typhimurium TA98, TA100, YG1041 at 10-200 microg/ml in culture broth. Bacteroides distasonis ATCC 8503, B. fragilis ATCC 25285, B. theataiotaomicron ATCC 29741, C. paraputrificum ATCC 26780, C. clostridiiforme ATCC 25537, Lactobacillus acidophilus ATCC 4356 and Enterococcus faecium ATCC 19434 were not inhibited by the above mentioned compounds in concentrations up to 200 microg/ml. The Ames Salmonella/microsome assay was employed to test the mutagenicity of the above-mentioned compounds using strains TA98 and TA100 in the presence and absence of Aroclor 1254-induced rat S9 mix. It was found that 4-ABP was mutagenic to both TA98 and TA100, and Bz was mutagenic to TA98 in the presence of rat S9 mix. 2-Aminobiphenyl, 3-ABP, and Bp were not mutagenic to both strains tested. 2-Aminobiphenyl and 3-ABP are chemical isomers of 4-ABP and are as strong as 4-ABP in inhibiting the growth of intestinal bacteria but not as mutagenic as 4-ABP. Evidence suggested that the mechanism of growth inhibition is not involved with the interaction of DNA that causes mutations, but rather on the electron transport system of these organisms.
Assuntos
Compostos de Aminobifenil/toxicidade , Benzidinas/toxicidade , Compostos de Bifenilo/toxicidade , Intestinos/microbiologia , Mutagênicos/toxicidade , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de MutagenicidadeRESUMO
Experiments were conducted to study the effect of a dietary supplement of dehulled adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) on the culture counts of some important groups of intestinal bacteria and their metabolism in the gastrointestinal (GI) tract of Sprague-Dawley rats. Rats were divided into four groups, and each group was fed a diet containing different levels of dehulled adlay for 30 days as follows: 0% (control), 5%, 20%, and 40%. All animals fed with adlay had normal healthy intestinal walls and no pathogenic signs whatsoever. There were no significant differences in body weight gain or the cecal pH between different groups of rats. Both the 20% and 40% groups had lower culture counts of enterics in their feces than the 5% and control groups, whereas the culture counts of fecal lactic acid bacteria were higher in feces of rats fed with adlay than in the control group. Cecal total short-chain fatty acid (SCFA) content and fecal SCFA were significantly higher in the 20% and 40% groups than in the control and 5% groups. All the adlay-fed rats had a higher fecal butyric acid concentration than the control rats. It is concluded that adlay has a significant influence on the growth of intestinal bacteria, which may ultimately affect the physiology and other functions of GI tracts of rats.