RESUMO
The influence of dietary caffeine on the genotoxicity of the cooked food mutagen 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) was evaluated using the host-mediated assay in mice. For four weeks, BALB/c mice were fed a purified diet with or without caffeine (0.01% wt/wt in the diet). In the host-mediated assay, Salmonella typhimurium TA98 was given intravenously immediately before an oral dose of MeIQx (1.5 mg/kg body wt). After one hour, the mice were killed, the Salmonellae were recovered from the liver, and the number of mutants (his+ revertants) were determined. Consumption of caffeine led to a 47% reduction in the number of mutants induced by MeIQx (p < 0.001). Subsequent in vitro experiments using S. typhimurium TA98 revealed that the capacity of hepatic S-9 fractions from the caffeine-fed mice to covert MeIQx to an active mutagen was reduced by approximately 35%. This effect was not attributable to caffeine in the S-9 preparation. These data suggest that consumption of caffeine modifies MeIQx mutagenicity by altering the spectrum of enzymes involved in its activation.
Assuntos
Cafeína/farmacologia , Carcinógenos/antagonistas & inibidores , Dieta , Quinoxalinas/antagonistas & inibidores , Animais , Cafeína/administração & dosagem , Carcinógenos/efeitos adversos , Sistema Enzimático do Citocromo P-450/análise , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Quinoxalinas/farmacologia , Salmonella typhimuriumRESUMO
Coal tar, a tumour initiator, and dithranol, a tumour promoter, are used in the treatment of psoriasis. Topical treatment of mice with pharmaceutical formulations of these two agents, at therapeutic doses, induced skin papillomas in a classical two-stage carcinogenesis protocol, while treatment with either agent alone did not. This finding has implications for the use of both agents in combination in the treatment of psoriasis.
Assuntos
Antralina/toxicidade , Carcinógenos/toxicidade , Alcatrão/toxicidade , Psoríase/tratamento farmacológico , Neoplasias Cutâneas/induzido quimicamente , Trifosfato de Adenosina/metabolismo , Administração Tópica , Animais , Antralina/administração & dosagem , Benzo(a)pireno/toxicidade , Carcinógenos/administração & dosagem , Alcatrão/administração & dosagem , DNA/biossíntese , DNA de Neoplasias/biossíntese , Feminino , Camundongos , Pomadas , Radioisótopos de Fósforo , Neoplasias Cutâneas/patologiaRESUMO
Female BALB/c mice were fed either a low (1%)-fat or one of three high-fat diets (containing an additional 25% (w/w) beef fat, hydrogenated vegetable oil or non-hydrogenated vegetable oil) for 4 wk. They were then orally treated with 10 mg 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)/kg body weight and killed 6 hr later. Consumption of the hydrogenated vegetable oil was accompanied by increased DNA adduct formation in mice. The abilities of hepatic S-9 preparations from mice fed the various diets to convert MeIQx to an active bacterial mutagen was assessed using Salmonella typhimurium TA98. Preparations from mice fed the high-fat diets exhibited significantly greater capacity to activate MeIQx than did those from low-fat-fed mice. The greatest increases were seen with S-9 from animals fed either beef fat or hydrogenated vegetable oil.
Assuntos
DNA/metabolismo , Gorduras na Dieta/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mutagênicos/metabolismo , Quinoxalinas/metabolismo , Administração Oral , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Mutagenicidade , Mutagênicos/toxicidade , Quinoxalinas/toxicidadeRESUMO
The effect of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid on the conversion of the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to its genotoxic metabolites was investigated using a modified bacterial mutation assay. The assay used Salmonella typhimurium TA98 as an indicator of the mutagenicity and hepatic post-mitochondrial fractions (S-9) from male Sprague-Dawley rats as the activating system. All three fatty acids inhibited the mutagenicity of IQ without effect on the uptake of the active metabolites and/or on the DNA repair processes within the bacterial cell. The activation of three other food mutagens, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and aflatoxin B1 (AFB1) was also inhibited by these fatty acids.
Assuntos
Ácido Araquidônico/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Contaminação de Alimentos , Microssomos Hepáticos/metabolismo , Mutagênicos/farmacocinética , Animais , Biotransformação , Reparo do DNA/efeitos dos fármacos , Técnicas In Vitro , Masculino , Testes de Mutagenicidade , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genéticaRESUMO
Hepatic microsomal fractions (microsomes) were prepared from male Sprague-Dawley rats. The effect of arachidonic acid on the conversion of the heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to its genotoxic metabolites was investigated using a modified bacterial mutation assay (indicator: Salmonella typhimurium TA98). Arachidonic acid inhibited the mutagenicity of IQ without effect on the uptake of the active metabolites and/or on the DNA-repair processes within the bacterial cell. The activation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and aflatoxin B1 (AFB1) was also inhibited by this polyunsaturated fatty acid.
Assuntos
Antimutagênicos/farmacologia , Ácido Araquidônico/farmacologia , Microssomos Hepáticos/metabolismo , Mutagênicos/metabolismo , Aflatoxina B1/metabolismo , Aflatoxina B1/farmacologia , Animais , Biotransformação , Reparo do DNA , Alimentos , Imidazóis/metabolismo , Imidazóis/farmacologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Testes de Mutagenicidade , Mutagênicos/farmacologia , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Salmonella typhimurium/efeitos dos fármacosRESUMO
Intraperitoneal treatment of female BALB/c mice with either phenobarbitone or beta-naphthoflavone led to the induction of various hepatic enzymes associated with xenobiotic metabolism and to increased abilities of hepatic S9 fractions to convert the dietary carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to an active bacterial mutagen. In the case of another carcinogen, aflatoxin B1 an increase in in vitro hepatic activation was seen only in mice treated with phenobarbitone. In contrast, pretreatment with either phenobarbitone or beta-naphthoflavone reduced the in vivo activity of both aflatoxin B1 and MeIQx in the host mediated bacterial mutation assay. These data indicate that, for some carcinogens at least, the host-mediated assay may be used to predict the carcinogenic consequences of hepatic enzyme induction.
Assuntos
Aflatoxinas/metabolismo , Carcinógenos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Mutagênicos/metabolismo , Quinoxalinas/metabolismo , Análise de Variância , Animais , Benzoflavonas/metabolismo , Indução Enzimática , Feminino , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Mutagênese , Testes de Mutagenicidade/métodos , Fenobarbital/metabolismo , Salmonella typhimurium , beta-NaftoflavonaRESUMO
Female BALB/c mice were fed a low fat diet (1% safflower oil, by weight) or one supplemented with 25% (by weight) of beef fat or olive oil. The abilities of these diets to modify the in vitro and in vivo hepatic conversion of the dietary carcinogens aflatoxin B1, 2-amino-3, 4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) to bacterial mutagens was evaluated. Dietary olive oil appeared to increase the metabolism of both MeIQ and Trp-P-2 to bacterial mutagens in vivo using the intrasanguineous host-mediated assay. Feeding mice either of the high-fat diets increased hepatic conversion of these two compounds to bacterial mutagens in vitro. Dietary fat had no effect on the metabolism of aflatoxin B1. Subsequent experiments suggested that the in vivo effects of dietary olive oil on MeIQ and Trp-P-2 mutagenesis were due to the induction of hepatic enzyme activities rather than to increased rates of uptake of the carcinogen from the gut-lumen.
Assuntos
Aflatoxinas/toxicidade , Carbolinas/toxicidade , Carcinógenos/toxicidade , Gorduras na Dieta/administração & dosagem , Quinolinas/toxicidade , Aflatoxina B1 , Aflatoxinas/metabolismo , Animais , Carbolinas/metabolismo , Carcinógenos/metabolismo , Feminino , Intestino Delgado/metabolismo , Fígado/anatomia & histologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Mutagenicidade , Mutagênicos , Tamanho do Órgão , Quinolinas/metabolismoRESUMO
The abilities of dietary fibre (wheat bran) or fat (olive oil) to modify the genotoxicity of radiolabelled MeIQ were evaluated in mice using in vivo and in vitro bacterial mutation assays. Bran reduced genotoxicity by restricting uptake of MeIQ from the gut lumen. In contrast, feeding mice a high fat diet led to increased hepatic conversion of MeIQ to an active genotoxin.
Assuntos
Gorduras na Dieta/farmacologia , Fibras na Dieta/farmacologia , Mutagênicos/metabolismo , Quinolinas/metabolismo , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Mutagenicidade , Mutagênicos/antagonistas & inibidores , Quinolinas/antagonistas & inibidores , Quinolinas/toxicidade , Salmonella typhimurium/efeitos dos fármacosRESUMO
Female BALB/c mice were fed diets containing equimolar amounts of quercetin or its glycoside, rutin, for 5 weeks. These mice were used either in host-mediated bacterial mutation assays or as sources of hepatic microsomes. In host-mediated bacterial mutation assays using radiolabelled mutagens, the heterocyclic amines 2-amino-3,5-dimethyl[4,5-f]imidazoquinoline (MeIQ) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) induced greater numbers of revertants in mice fed either of the flavonoid diets compared with control. Experiments using hepatic microsomes revealed that although feeding mice either flavonoid produced slight changes in some parameters of hepatic xenobiotic metabolism (mixed function oxidase and glutathione transferase activities), microsomes from quercetin-fed mice were more potent activators of both MeIQ and Trp-P-2 compared with microsomes from control or rutin-fed mice. This difference in microsomal ability may be due to the different biological availability of the two flavonoids within the gastrointestinal tract.
Assuntos
Flavonoides/farmacologia , Quercetina/farmacologia , Quinolinas/toxicidade , Animais , Carbolinas/toxicidade , Dano ao DNA , Dieta , Feminino , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Testes de Mutagenicidade , Mutagênicos , Quinolinas/antagonistas & inibidores , Rutina/farmacologia , XenobióticosRESUMO
Female BALB/c mice were administered intragastrically with equimolar amounts of either [2-14C]2-amino-3,8-dimethyl-[4,5-f]quinoxaline (MeIQx) or 2-acetylamino[9-14C]fluorene (2AAF). DNA was isolated from tissues of mice killed either 6 or 24 h after administration. Analysis of lvier DNA nucleotide digests by HPLC analysis revealed that all of the radioactivity was attributable to adduct formation. The specific activities of DNA samples were converted to covalent binding indices (CBI, mumol adduct per mol DNA nucleotides/mmol chemical applied per kg animal body weight). CBI values of 25 and 9 were determined for 2AAF and MeIQx in the livers of mice killed 6 h after dosing. The values were in general agreement with the moderate carcinogenic potency of these compounds. The specific activities of DNA preparations obtained from the kidneys, spleens, stomachs, small intestines and large intestines of mice treated with MeIQx and killed 6 h after dosing were 5- to 35-times less than those obtained with the liver. DNA isolated from the lungs (a target organ for MeIQx tumorigenicity) of MeIQx-treated mice was not radiolabelled at the limit of detection (CBI less than 0.3). With the exception of the gastrointestinal tract, the specific activities of DNA samples isolated from mice killed 6 h after administration were higher than those from mice killed after 24 h.
Assuntos
DNA/metabolismo , Mutagênicos/metabolismo , Quinoxalinas/metabolismo , Animais , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , DNA/isolamento & purificação , Feminino , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Quinoxalinas/farmacocinética , Técnica de Diluição de Radioisótopos , Distribuição TecidualRESUMO
Female BALB/c mice were fed either a fibre-free diet or one supplemented with 30% wheat-bran for 5 weeks. The ability of these mice to convert MeIQ to a bacterial mutagen in vivo was determined using intrasanguinous host-mediated bacterial mutation assays. Less mutagenic activity was detected in the livers of mice fed the bran-supplemented diet compared with those fed the fibre-free diet. Subsequent experiments demonstrated that the effect of brain was not due to modifications in hepatic metabolism, but to changes in uptake of MeIQ from the gastrointestinal tract.
Assuntos
Fibras na Dieta/fisiologia , Mutação/efeitos dos fármacos , Quinolinas/farmacocinética , Administração Oral , Animais , Biotransformação , Mucosa Gástrica/metabolismo , Absorção Intestinal , Intestino Delgado/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Quinolinas/toxicidade , Distribuição Tecidual , TriticumRESUMO
The kinetics of distribution of radiolabelled [2-14C]IQ (2-amino-3-methylimidazo[4,5-f]quinoline) and [2-14C]MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline) following the oral administration to BALB/c mice of single doses were studied. Both compounds were taken up into the blood-stream and other tissues rapidly after administration and approximately 20-25% of the radioactive dose of IQ or MeIQx was excreted in urine over 6 h, reflecting the rapid absorption of the mutagens. Significantly greater levels of MeIQx than IQ were isolated from the lungs and blood of treated mice. In studies of the uptake of IQ from closed sections of the gut, little IQ was absorbed from the stomach. Although there was some evidence that it could be absorbed from the large intestine, the primary site of IQ absorption was the small intestine.
Assuntos
Carcinógenos/farmacocinética , Quinolinas/farmacocinética , Quinoxalinas/farmacocinética , Administração Oral , Animais , Radioisótopos de Carbono , Carcinógenos/urina , Cromatografia em Camada Fina , Feminino , Conteúdo Gastrointestinal/análise , Absorção Intestinal , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/urina , Quinoxalinas/urina , Distribuição TecidualRESUMO
Hepatic microsomal fractions (microsomes) were prepared from female BALB/c mice. The potential of caffeine to modify the ability of microsomes to convert the heterocyclic aromatic amines MeIQ, Trp-P-2 and MeIQx, to bacterial mutagens (indicator: Salmonella typhimurium TA98) was investigated. Caffeine inhibited mutagenicity and did so by inhibiting microsomal metabolism of the three compounds, rather than by altering uptake of the active mutagens and/or interacting with the DNA repair processes in the bacterial cell. Notional Ki values determined for the three heterocyclic amines were similar, suggesting that caffeine inhibits at a stage common to the metabolism of all three compounds.
Assuntos
Cafeína/farmacologia , Microssomos Hepáticos/metabolismo , Mutagênicos/metabolismo , Animais , Biotransformação , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos , Testes de Mutagenicidade , Mutagênicos/farmacologia , Valores de Referência , Salmonella typhimurium/efeitos dos fármacosAssuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Flavonoides/farmacologia , Intestinos/microbiologia , Fígado/enzimologia , Oxigenases de Função Mista/metabolismo , Quercetina/farmacologia , Rutina/farmacologia , Animais , Dieta , Feminino , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/enzimologiaRESUMO
Male Ola:Sprague-Dawley rats were fed diets containing either low or high levels of fats. After being fed these diets for 4 weeks, the rats were killed and individual hepatic postmitochondrial (S9) fractions were prepared. The ability of these fractions to convert the heterocyclic aromatic amines (HAAs)--2-amino-3-methylimidazo[4,5-f]quinoline; 2-amino-3,4-dimethylimidazo[4,5-f] quinoline; and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (compounds produced during the cooking of proteinaceous food)--to bacterial mutagens was studied, with the use of Salmonella typhimurium TA98 as indicator. Fractions from rats fed high-fat diets exhibited a greater ability to activate the HAAs than did those from rats fed the low-fat diet. The magnitude of the increase was dependent on the type of fat used.
Assuntos
Gorduras na Dieta/administração & dosagem , Mitocôndrias Hepáticas/metabolismo , Mutagênicos/toxicidade , Animais , Arocloros/farmacologia , Biotransformação , Gorduras na Dieta/farmacologia , Masculino , Testes de Mutagenicidade , Ratos , Ratos EndogâmicosRESUMO
The biogenic amines tryptamine, 5-hydroxytryptamine, tyramine and histamine were assessed for their abilities to modify the genotoxicity of the cooked-food mutagens IQ, MeIQ, MeIQx, Trp-P-1 and Trp-P-2. These measurements were made using a bacterial mutation assay with hepatic fractions from either SWR mice or DSN Syrian hamsters as the activating system and Salmonella typhimurium TA98 as the indicator organism. Although histamine had very little effect on the genotoxicity of these mutagens, the other amines reduced genotoxicity, with tryptamine and 5-hydroxytryptamine exerting the greatest effect. Generally the amines exhibited greater potency when S-9 fractions from mice rather than from hamsters were used.
Assuntos
Aminas Biogênicas/farmacologia , Alimentos , Mutagênicos/antagonistas & inibidores , Animais , Biotransformação , Culinária , Cricetinae , Histamina/farmacologia , Masculino , Mesocricetus , Camundongos , Testes de Mutagenicidade , Mutagênicos/metabolismo , Serotonina/farmacologia , Especificidade da Espécie , Triptaminas/farmacologia , Tiramina/farmacologiaRESUMO
Groups of Sprague-Dawley rats were fed on diets containing increasing amounts of beef dripping, but having a constant cholesterol content. One group of rats was fed on a diet containing no dripping and no added cholesterol (control). We have studied the ability of individual hepatic S9 preparations to activate the cooked food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQX) to bacterial mutagens using Salmonella typhimurium TA98 as indicator. Hepatic preparations from animals fed on a high cholesterol, low-fat diet were less effective in activating the mutagens than preparations from rats fed on the control diet. It was also observed that the capacity of hepatic preparations to activate these mutagens increased as the amount of dripping in the diet increased. These results suggest that it is the triglyceride rather than the cholesterol content of beef dripping which promotes increased mutagen activation capacity in the liver.
Assuntos
Colesterol na Dieta/farmacologia , Gorduras na Dieta/farmacologia , Microssomos Hepáticos/metabolismo , Mutagênicos/farmacologia , Mutação , Quinolinas/farmacologia , Quinoxalinas/farmacologia , Animais , Biotransformação , Bovinos , Temperatura Alta , Masculino , Testes de Mutagenicidade , Mutagênicos/metabolismo , Quinolinas/metabolismo , Quinoxalinas/metabolismo , Ratos , Ratos Endogâmicos , Salmonella typhimurium/efeitos dos fármacosRESUMO
A method of maintaining the microflora obtained from the hypochlorhydric stomach of a patient suffering from hypogammaglobulinaemia has been developed using continuous culture (chemostat) techniques. The culture was maintained at pH 8.0 (the pH of the original gastric juice) and subsequently at pH 7.0 and pH 6.0. Throughout the experiment the total population of the culture remained constant, although the populations of individual bacterial strains varied. Two enzyme parameters, nitrate reductase and beta-glycosidase, were also measured. Optimal enzyme activity was observed at pH 7.0. The results suggest that at the physiological pH values found in hypochlorhydric patients, the gastric flora may play a role in the generation of genotoxins and/or their precursors.
RESUMO
The ability of 3 plant flavonoids (morin, myricetin and quercetin) and 4 polyphenolic acids (caffeic acid, chlorogenic acid, ellagic acid and ferulic acid) to inhibit the genotoxic effects of a number of cooked-food mutagens (IQ, MeIQ, MeIQx, Trp-P-1 and Trp-P-2), was investigated in a bacterial mutation assay using Salmonella typhimurium TA98 as indicator and hepatic S9 mixes from either SWR mice or Syrian hamsters as metabolic activating systems. Although the polyphenolic acids failed to have an effect, the flavonoids generally inhibited IQ, MeIQ, MeIQx and Trp-P-1 induced mutagenesis in a dose-dependent manner, irrespective of the source of S9. This was not the case with Trp-P-2 where the flavonoids were only observed to inhibit when SWR mouse S9 but not Syrian hamster S9 was used. Of the 3 compounds, myricetin and quercetin were superior to morin in their inhibitory capacity.