RESUMO
A Phase II chemoprevention trial was carried out in Qidong, Jiangsu Province, People's Republic of China. The recruited subjects, all of whom were positive for serum aflatoxin-albumin adducts, were divided into three treatment arms: placebo; oltipraz ([5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione]) given daily at 125 mg p.o.; and oltipraz given once per week at 500 mg p.o. Besides biomarkers related to aflatoxin B(1) exposure, the genotoxicity of blind-coded urine XAD-2 concentrates was evaluated in 201 subjects on the fifth and seventh week of intervention. Genotoxicity was assessed both in the Ames reversion test in strain YG1024 of Salmonella typhimurium, in the presence of an exogenous metabolic system (S9 mix), with or without beta-glucuronidase, and in a DNA repair test in Escherichia coli. Heating of concentrated urine samples or of cigarette smoke condensates was discovered to result in a significant enhancement of their mutagenicity. It was also found that the mutagenicity of condensates from the most extensively used brands of cigarettes in Qidong was much lower than that of Western cigarette brands. Urine mutagenicity was unrelated to treatment with oltipraz, intervention time, gender, and supplement of S9 mix with beta-glucuronidase. Mutagenicity was significantly but variably higher in cigarette smokers than in nonsmokers, which suggests that the urinary excretion of mutagens in the examined population was not exclusively attributable to smoking. Nevertheless, within smokers (28% of the recruited subjects; 67% of all males), the mutagenic potency was significantly correlated with the self-reported number of cigarettes smoked per day and, even more sharply, with the cotinine concentrations in urines. In conclusion, this study demonstrated the validity of urine mutagenicity assays as a biomarker of tobacco smoke exposure that can be investigated on a relatively large scale in chemoprevention trials and provided evidence that oltipraz treatment had no influence on this parameter in the examined population.
Assuntos
Biomarcadores/análise , Pirazinas/farmacologia , Fumar/efeitos adversos , Administração Oral , Adulto , Quimioprevenção , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Feminino , Humanos , Masculino , Testes de Mutagenicidade , Mutagênicos/análise , Neoplasias/prevenção & controle , Pirazinas/administração & dosagem , Reprodutibilidade dos Testes , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Tionas , Tiofenos , UrinaRESUMO
Chemoprevention opens new perspectives in the prevention of cancer and other chronic degenerative diseases associated with tobacco smoking, exploitable in current smokers and, even more, in exsmokers and passive smokers. Evaluation of biomarkers in animal models is an essential step for the preclinical assessment of efficacy and safety of potential chemopreventive agents. Groups of Sprague Dawley rats were exposed whole body to a mixture of mainstream and sidestream cigarette smoke for 28 consecutive days. Five chemopreventive agents were given either with drinking water (N-acetyl-L-cysteine, 1 g/kg body weight/day) or with the diet (1,2-dithiole-3-thione, 400 mg; Oltipraz, 400 mg; phenethyl isothiocyanate, 500 mg; and 5,6-benzoflavone, 500 mg/kg diet). The monitored biomarkers included: DNA adducts in bronchoalveolar lavage cells, tracheal epithelium, lung and heart; oxidative damage to pulmonary DNA; hemoglobin adducts of 4-aminobiphenyl and benzo(a)pyrene-7,8-diol-9,10-epoxide; micronucleated and polynucleated alveolar macrophages and micronucleated polychromatic erythrocytes in bone marrow. Exposure of rats to smoke resulted in dramatic alterations of all investigated parameters. N-Acetyl-L-cysteine, phenylethyl isothiocyanate, and 5,6-benzoflavone exerted a significant protective effect on all alterations. 1,2-Dithiole-3-thione was a less effective inhibitor and exhibited both a systemic toxicity and genotoxicity in alveolar macrophages, whereas its substituted analogue Oltipraz showed limited protective effects in this model. Interestingly, combination of N-acetyl-L-cysteine with Oltipraz was the most potent treatment, resulting in an additive or more than additive inhibition of smoke-related DNA adducts in the lung and hemoglobin adducts. These results provide evidence for the differential ability of test agents to modulate smoke-related biomarkers in the respiratory tract and other body compartments and highlight the potential advantages in combining chemopreventive agents working with distinctive mechanisms.
Assuntos
Anticarcinógenos/farmacologia , Nicotiana/efeitos adversos , Plantas Tóxicas , Fumaça/efeitos adversos , Fumar/metabolismo , Acetilcisteína/farmacologia , Animais , Biomarcadores/análise , Adutos de DNA/antagonistas & inibidores , Adutos de DNA/metabolismo , Dano ao DNA , Ingestão de Alimentos/efeitos dos fármacos , Hemoglobinas/metabolismo , Exposição por Inalação , Pulmão/metabolismo , Masculino , Micronúcleos com Defeito Cromossômico , Oxirredução , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Fumar/sangue , Tionas , Tiofenos , Poluição por Fumaça de Tabaco , Aumento de Peso/efeitos dos fármacosRESUMO
In spite of the major role played by cigarette smoking in the epidemiology of lung cancer, it is very difficult to reproduce the carcinogenicity of this complex mixture in animal models. We implemented a series of pilot experiments in three mouse strains, exposed either to environmental cigarette smoke (ECS) or mainstream cigarette smoke (MCS) or its condensate (MCSC). The whole-body exposure of Aroclor-treated A/J mice to ECS resulted in a rapid and potent induction of micronuclei in peripheral blood erythrocytes. After 6 months of exposure, 6 h a day, followed by 4 months of recovery in filtered air, both lung tumor incidence and multiplicity were significantly increased as compared to sham-exposed mice (77.8% vs. 22.2%, and 1.11+/-0.26 vs. 0.22+/-0.15, means +/- SE). Multiple i.p. injections of butylated hydroxytoluene did not significantly enhance the tumor yield. Another experiment confirmed the responsiveness of A/J mice exposed to ECS for 5 months, followed by 4 months of recovery in air (75.0% vs. 25.0%, and 1.05+/-0.17 vs. 0.25+/-0.10). In contrast, the increase in lung tumor yield after exposure to ECS for 2 months, followed by recovery in air for 7 months, was not significant, and the continuous exposure to ECS for 9 months was totally ineffective. These data, in agreement with previous results of others, show that exposure of A/J mice to ECS for 5-6 months, followed by recovery in air for 4 months, is successful in inducing a weak but significant and reproducible increase in lung tumor yield. Furthermore, the simultaneous exposure to the light emitted by halogen quartz bulbs for 9 months and to ECS for 5 months, followed by 4 months in air, was again weakly tumorigenic (incidence of 55.0% and multiplicity of 0.75+/-0.19), whereas exposure to both ECS and light for 9 months was devoid of effect. The whole-body exposure of A/J mice to MCS, 1 h a day for 5 months, or weekly i.p. injections of MCSC for 5 months, followed in both cases by 4 months of recovery in air, failed to enhance the lung tumor yield. The whole-body exposure of SKH-1 hairless mice to ECS for 6 months, followed by exposure to halogen light for 8 months, resulted in the formation of multiple skin tumors but failed to produce lung tumors. The whole-body exposure of C57BL/6 mice to ECS for 6 months failed to induce any lung tumor but caused alopecia, gray hair, and hair bulb cell apoptosis, which were prevented by the oral administration of N-acetylcysteine.
Assuntos
Adenoma/etiologia , Neoplasias Pulmonares/etiologia , Fumar/efeitos adversos , Acetilcisteína/farmacologia , Adenoma/genética , Adenoma/patologia , Animais , Peso Corporal , Hidroxitolueno Butilado/toxicidade , Análise Citogenética , Dano ao DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Feminino , Incidência , Injeções Intraperitoneais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Pelados , Camundongos Endogâmicos C57BL , Projetos PilotoRESUMO
Chronic degenerative diseases, including cancer, have a multifactorial origin. An intricate network connects each disease with multiple risk factors and also with multiple protective factors. From the point of view of preventive medicine, this implies that removal of a single risk factor will have a beneficial impact on the epidemiology of several diseases. However, in contrast to the situation in infectious diseases, it will never be possible to eradicate any chronic degenerative disease in this way, because each of them is associated with other risk factors at the same time. Similarly, a single protective factor can decrease the risk of contracting different diseases, and the risk of developing a single disease can be attenuated by different protective factors, often in a coordinated fashion. It is thus evident that cancer can be prevented not only by avoiding exposure to recognized risk factors, but also, as a complementary approach referred to as chemoprevention, by favouring the intake of protective factors and by fortifying the physiological defences of the host organism. Chemoprevention can be applied in a primary prevention setting when it is addressed to healthy individuals with the goal of inhibiting occurrence of the disease. Conversely, it is applied in a secondary prevention setting when it is addressed to individuals affected by premalignant tumours, with the goal of reversing the carcinogenesis process. A rational use of chemopreventive agents is based not only on the assessment of their efficacy and safety but also on understanding of their mechanisms of action. A detailed classification is proposed, which covers a variety of mechanisms interfering with different phases of mutagenesis and carcinogenesis. However, this sequence of events does not fit in with a rigid scheme, and several mechanisms, such as inhibition of genotoxic effects, antioxidant activity and scavenging of free radicals, inhibition of cell proliferation, and signal transduction modulation are reiterated several times throughout evolution of these processes. Some of these mechanisms are also involved in advanced stages of tumour progression towards malignancy, invasion and metastasis, and can therefore conveniently be applied for the tertiary prevention of cancer. Most inhibitors work through multiple mechanisms, examples of which are given for 18 chemopreventive agents.
Assuntos
Neoplasias/prevenção & controle , Anticarcinógenos/uso terapêutico , Antimutagênicos/uso terapêutico , Humanos , Neoplasias/epidemiologia , Fatores de RiscoRESUMO
Traditional halogen tungsten lamps, which are extensively used worldwide for the illumination of indoor environments, have a quartz bulb which transmits not only visible light but also ultraviolet (UV) light. Due to the output of far-UV wavelengths, halogen lamps were found in previous studies to be potently genotoxic in bacteria, clastogenic in cultured human cells, and carcinogenic in hairless mice. This discovery prompted the launching of new halogen lamps, known as UV-Stop, UV-Block, or similar trade names, which have the quartz glass treated in such a way to reduce its permeability to UV radiation. Surprisingly, these lamps are advertised for attenuating discolouration of UV-sensitive materials, such as fabrics, paintings, works of art and furniture, whereas protection of the human skin from potential carcinogenic risks is overlooked. We tested forty-seven 12 V-powered lamps with treated quartz bulb, which were made available by five producers as blind-coded samples. After exposure to either 1000 lx for 30 min or 2500 lx for 60 min, the 50 W lamps from two producers were borderline mutagenic in strains TA100 and TA104 of S. typhimurium, and induced an evident and dose-related DNA damage in the E. coli strain CM871 (uvrA- recA- lexA-), as compared to its isogenic, DNA repair-proficient counterpart WP2. The 50 W lamps supplied by the other three producers also induced a significant genotoxic damage, but only after exposure for 60 min at illuminance levels of 2500 lx or higher. In calibration experiments, one of these three lamp brands was found to induce in 60 min a genotoxic damage which was equivalent to the one induced in just 55 s by a traditional halogen lamp. Therefore, the new types of lamps with treated quartz bulbs provide an appreciable step forward in the safety of halogen lamps, but some output of genotoxic UV radiations does still occur. Moreover, the lamps manufactured by different producers are not equally effective to this respect. By comparison, the simple application of a glass cover to a traditional halogen lamp completely prevented genotoxic effects, even after 60 min of exposure at an illuminance of 10,000 lx. Suitable regulations are urgently needed for controlling the biological safety or artificial illumination systems.
Assuntos
Escherichia coli/efeitos da radiação , Iluminação , Salmonella typhimurium/efeitos da radiação , Tungstênio , Raios Ultravioleta , Animais , Dano ao DNA , DNA Bacteriano/efeitos da radiação , Escherichia coli/genética , Halogênios , Humanos , Iluminação/efeitos adversos , Camundongos , Camundongos Pelados , Testes de Mutagenicidade/métodos , Tungstênio/efeitos adversosRESUMO
Estimates of the overall reducing capacity of hexavalent chromium(VI) in some human body compartments were made by relating the specific reducing activity of body fluids, cell populations or organs to their average volume, number, or weight. Although these data do not have absolute precision or universal applicability, they provide a rationale for predicting and interpreting the health effects of chromium(VI). The available evidence strongly indicates that chromium(VI) reduction in body fluids and long-lived non-target cells is expected to greatly attenuate its potential toxicity and genotoxicity, to imprint a threshold character to the carcinogenesis process, and to restrict the possible targets of its activity. For example, the chromium(VI) sequestering capacity of whole blood (187-234 mg per individual) and the reducing capacity of red blood cells (at least 93-128 mg) explain why this metal is not a systemic toxicant, except at very high doses, and also explain its lack of carcinogenicity at a distance from the portal of entry into the organism. Reduction by fluids in the digestive tract, e.g. by saliva (0.7-2.1 mg/day) and gastric juice (at least 84-88 mg/day), and sequestration by intestinal bacteria (11-24 mg eliminated daily with feces) account for the poor intestinal absorption of chromium(VI). The chromium(VI) escaping reduction in the digestive tract will be detoxified in the blood of the portal vein system and then in the liver, having an overall reducing capacity of 3300 mg. These processes give reasons for the poor oral toxicity of chromium(VI) and its lack of carcinogenicity when introduced by the oral route or swallowed following reflux from the respiratory tract. In terminal airways chromium(VI) is reduced in the epithelial lining fluid (0.9-1.8 mg) and in pulmonary alveolar macrophages (136 mg). The peripheral lung parenchyma has an overall reducing capacity of 260 mg chromium(VI), with a slightly higher specific activity as compared to the bronchial tree. Therefore, even in the respiratory tract, which is the only consistent target of chromium(VI) carcinogenicity in humans (lung and sinonasal cavities), there are barriers hampering its carcinogenicity. These hurdles could be only overwhelmed under conditions of massive exposure by inhalation, as it occurred in certain work environments prior to the implementation of suitable industrial hygiene measures.
Assuntos
Compartimentos de Líquidos Corporais , Carcinógenos Ambientais/farmacocinética , Cromo/farmacocinética , Disponibilidade Biológica , Sangue/metabolismo , Carcinógenos Ambientais/toxicidade , Cromatos/farmacocinética , Cromatos/toxicidade , Cromo/toxicidade , Fezes/microbiologia , Feminino , Humanos , Fígado/metabolismo , Macrófagos Alveolares/metabolismo , Masculino , Especificidade de Órgãos , Oxirredução , Sistema Respiratório/metabolismoRESUMO
Urinary genotoxicity assays measure the internal dose of genotoxic carcinogens, thereby providing a particularly sensitive endpoint for selecting cohorts of individuals exposed to cigarette smoke or other mutagens excreted with urines, as well as for evaluating the modulation of this parameter after administration of chemopreventive agents. Mutagenicity of urines was investigated in smoking Italian volunteers, who received oral N-acetylcysteine (NAC) at the same doses which are usually prescribed for the long-term treatment of chronic bronchitis. The daily excretion of mutagens, concentrated on XAD-2 columns and tested in Salmonella typhimurium YG1024 with S9 mix, was significantly and remarkably decreased by NAC in the majority of the subjects examined so far. Time-course experiments showed that this effect starts since the first day of drug administration and reverses when treatment is withdrawn. In addition, NAC administration almost totally prevented urinary genotoxicity in one subject whose concentrated urines induced a differential lethality in Escherichia coli strains having distinctive DNA repair capacities. The decrease of urinary genotoxicity produced by NAC in the majority of smokers correlates with the ability of this thiol to prevent tumors and to affect a variety of intermediate biomarkers in animal models. Modulation of the urinary excretion of mutagens is one of the biomarkers evaluated in two ongoing Phase II chemoprevention trials. One study involves the oral administration of NAC in Dutch smokers. The pretreatment urine samples of all the subjects so far recruited are clearly mutagenic. The other study involves the oral administration of the dithiolethione oltipraz to individuals living in the Qidong County of the People's Republic of China, an area of high endemy for HBV infection and of high exposure to aflatoxins. Additionally, a large proportion of the recruited male subjects are smokers. A total of 500 urine specimens will be assayed from 240 subjects according to a complex protocol arranged in three consecutive phases.
Assuntos
Anticarcinógenos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Pulmonares/prevenção & controle , Mutagênicos/análise , Fumar/urina , Acetilcisteína/uso terapêutico , Adulto , Quimioprevenção , China , Ensaios Clínicos Fase II como Assunto , Estudos de Coortes , Reparo do DNA , Feminino , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Testes de Mutagenicidade , Países Baixos , Pirazinas/uso terapêutico , Projetos de Pesquisa , Fumar/efeitos adversos , Tionas , TiofenosRESUMO
Marine sponges do not appear to suffer from neoplastic diseases, in spite of possible high exposures resulting from their nature as sessile bottom filter feeders which pump large volumes of sea water. The assessment of several parameters related to the biotransformation of mutagens/carcinogens showed that the metabolic machinery of sponge medulla cells is mainly oriented towards detoxification, with some differences depending on species (Geodia cydonium or Tethya aurantium). Glutathione (GSH) levels were unexpectedly high in these cells, especially in Geodia, in which the concentration of this tripeptide was more than twice that measured in liver preparations from untreated rats, at least when related to the protein content. The oxidoreductive enzyme activities involved in the glutathione cycle were balanced in such a way as to favour a high GSH: oxidized glutathione (GSSG) ratio. GSH S-transferase activity was conversely rather low, compared to that of rat liver, and the dehydrogenases involved in the hexose monophosphate shunt were high in Tethya but low in Geodia. The metabolism of mutagens was investigated by using the Salmonella typhimurium his- strains TA100, TA98 and YG1024. Sponge S12 fractions failed to activate aflatoxin B1, benzo[a]pyrene and the two heterocyclic amines 3-amino-1-methyl-5H-pyrido[4,3-b]indole and 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoline. Although far less efficiently than untreated rat liver S12 fractions, Geodia and especially Tethya preparations weakly activated the three aromatic amines 2-acetyl-aminofluorene, 2-aminofluorene and 2-aminoanthracene. On the other hand, sponge S12 fractions were remarkably efficient in decreasing the mutagenic potency of the direct-acting mutagens 4-nitroquinoline 1-oxide and sodium dichromate.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Inativação Metabólica , Mutagênicos/metabolismo , Mutagênicos/toxicidade , Poríferos/metabolismo , 2-Acetilaminofluoreno/metabolismo , 2-Acetilaminofluoreno/toxicidade , Aflatoxina B1/metabolismo , Aflatoxina B1/toxicidade , Animais , Benzo(a)pireno/metabolismo , Benzo(a)pireno/toxicidade , Biotransformação , Carbolinas/metabolismo , Carbolinas/toxicidade , Glutationa/análogos & derivados , Glutationa/metabolismo , Dissulfeto de Glutationa , Glutationa Transferase/metabolismo , Microssomos Hepáticos/metabolismo , Mutagênicos/farmacocinética , Quinolinas/metabolismo , Quinolinas/toxicidade , Ratos , Salmonella typhimurium/efeitos dos fármacos , Especificidade da Espécie , Vincristina/farmacocinéticaRESUMO
The thiol N-acetylcysteine (NAC), now under clinical trial for cancer chemoprevention both in Europe (project Euroscan) and in the US (National Cancer Institute), has been shown during the past decade to exert protective effects in a variety of experimental test systems. NAC inhibited spontaneous mutagenicity and that induced by a number of chemical compounds and complex mixtures. Moreover, NAC significantly decreased the incidence of neoplastic and preneoplastic lesions induced by several chemical carcinogens in rodents (mice, rats, hamsters), e.g., in lung, trachea, colon, liver, mammary gland, Zymbal gland, bladder and skin. Our studies provided evidence that multiple mechanisms contribute to NAC antimutagenicity and anticarcinogenicity. They include extracellular mechanisms, such as detoxification of reactive compounds due to the nucleophilic and antioxidant properties of NAC, inhibition of nitrosation products, and enhancement of thiol concentration in intestinal bacteria; trapping and enhanced detoxification of carcinogens in long-lived non-target cells, such as erythrocytes and bronchoalveolar lavage cells; mechanisms working in the cytoplasm of target cells, such as replenishment of GSH stores, modulation of metabolism of mutagens/carcinogens, blocking of electrophiles, and scavenging of reactive oxygen species; and nuclear effects, such as inhibition of DNA adduction by metabolites of carcinogens, inhibition of "spontaneous" mutations, attenuation of carcinogen-induced DNA damage, and protection of nuclear enzymes, such as poly(ADP-ribose) polymerase.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Acetilcisteína/uso terapêutico , Anticarcinógenos/uso terapêutico , Animais , Biomarcadores/química , Cricetinae , Citoplasma/efeitos dos fármacos , Humanos , Inativação Metabólica , Camundongos , Testes de Mutagenicidade , Invasividade Neoplásica , Metástase Neoplásica , RatosRESUMO
The aromatic amines 2-aminofluorene (2AF), 2-acetylaminofluorene, and 2-aminoanthracene, and the heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, and 3-amino-1-methyl-SH-pyrido[4,3-b]indole (Trp-P-2) were activated by rat liver cytosolic fractions to form mutagenic metabolites in Salmonella typhimurium strains TA98, TA98NR, and TA98/1,8-DNP6. In the case of the Trp-P-2, the cytosolic activation was even more potent than the microsomal activation, which is classically ascribed to N-hydroxylation and subsequent esterification. The cytosolic activation was a) NADPH-dependent, b) induced by pretreatment of rats with 3-methylcholanthrene and especially Aroclor 1254 but not by phenobarbital, and c) inhibited by dicoumarol. The hypothesis is that, following a preliminary oxidative step in the cytosol (pure cytosolic activation) or in microsomes via prostaglandin H synthase (mixed microsomal-cytosolic activation), an oxidized intermediate of amino compounds may serve as substrate for DT diaphorase activity and bielectronically reduced to the corresponding N-hydroxyamino derivative. Purified DT diaphorase, in the presence of either NADPH or NADH as electron donor, produced mutagenic derivatives from IQ and Trp-P-2. An NADPH-dependent activation of Trp-P-2 also occurred in the liver cytosol of woodchucks (Marmota monax), but was not inhibited by dicoumarol. As previously demonstrated with liver S-12 fractions in both humans and woodchucks, the cytosolic activation of Trp-P-2 was enhanced in animals affected by hepatitis B virus infection. This enhanced metabolism, which persisted even after appearance of primary hepatocellular carcinoma in virus carriers, is likely to be ascribed to mechanisms other than DT diaphorase induction, such as glutathione depletion.
Assuntos
Aminas/metabolismo , Citosol/metabolismo , Dicumarol/farmacologia , Hepatite B/metabolismo , Compostos Heterocíclicos/metabolismo , Fígado/metabolismo , Aminas/antagonistas & inibidores , Animais , Sinergismo Farmacológico , Transporte de Elétrons , Compostos Heterocíclicos/antagonistas & inibidores , Fígado/ultraestrutura , Masculino , Testes de Mutagenicidade , Mutagênicos/metabolismo , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NADP/metabolismo , Ratos , Ratos Sprague-Dawley , Salmonella typhimurium/genéticaRESUMO
Thirty-four compounds belonging to various chemical classes were assayed for the ability to modulate the 'spontaneous' mutagenicity in strain TA104 of S. typhimurium, and 17 of them were also assayed in TA102. All test agents, many of which were already known or suspected to act as inhibitors of induced mutagenicity, had been previously monitored in our laboratory for antimutagenicity towards either 4-nitroquinoline 1-oxide in TA100 and/or cigarette smoke in TA98 with S9 mix. A considerable proportion of test compounds decreased the number of spontaneous revertants in TA104 (44.1%) and/or TA102 (41.2%) to a significant extent, with dose-related and reproducible effects. In almost all cases the antimutagenic effect was genuine and not related to bacterial killing or growth inhibition. The results obtained suggest that the DNA repair background plays a prominent role in the genesis of spontaneous mutations in these strains, containing the hisG428 mutation which is typically reverted by oxidative mutagens. Due to its theoretical and practical implications, the finding that several chemopreventive agents can attenuate the rate of spontaneous reversion deserves attention.
Assuntos
Antimutagênicos/farmacologia , Mutagênese/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Especificidade da EspécieRESUMO
Two antimutagenicity databases were prepared by applying a co-treatment procedure to the Salmonella reversion assay. Ninety compounds belonging to various chemical classes were quantitatively tested for antimutagenicity towards the direct-acting mutagen 4-nitroquinoline 1-oxide (4NQO) in strain TA100 of S. typhimurium and 63 of them were additionally tested for antimutagenicity towards unfractionated mainstream cigarette smoke (CS) in strain TA98, in the presence of S9 mix. Twelve compounds (13.3%) inhibited 4NQO mutagenicity by at least 50%, with a MID50 (dose inhibiting 50% of mutagenicity) varying over a 1226-fold range. Twenty-six compounds (41.3%) inhibited CS mutagenicity, with a MID50 varying over a 520-fold range. Three compounds only, i.e., bilirubin, curcumin and myricetin, were capable of inhibiting the mutagenicities of both 4NQO and CS. However, myricetin and the other flavonoid rutin were at the same time mutagenic by inducing frameshift mutations following metabolic activation. There was a rather rigorous selectivity of antimutagenicity data depending on the chemical class of inhibitors and it was possible to discriminate protective effects within several pairs or series of structurally related compounds. For instance, all eight thiols and aminothiols inhibited 4NQO mutagenicity, which contrasted with the inactivity of the remaining 17 sulfur compounds tested, all of them lacking a free sulfhydryl group. The mutagenicity of CS was consistently inhibited by the majority of phenols (eight out of 10 tested) and by all two isothiocyanates, two dithiocarbamates, three indole derivatives, three tetrapyrrole compounds and three flavonoids tested. Although the results obtained cannot be extrapolated to other mutagens or test systems, they may provide a useful source of information for research in the area of antimutagenesis and for the development of chemopreventive agents.
Assuntos
4-Nitroquinolina-1-Óxido/toxicidade , Antimutagênicos/farmacologia , Sistemas de Informação , Nicotiana , Plantas Tóxicas , Fumaça/efeitos adversos , Testes de Mutagenicidade , Relação Estrutura-AtividadeRESUMO
This article reviews literature data concerning the genotoxicity of 29 mercury-containing agents, including laboratory compounds as well as ingredients of preparations used as fungicides, dyes, disinfectants and drugs. A variety of genetic end-points were investigated in bacteria, yeasts, moulds, plants, insects, cultured cells from fishes, rodents or humans, aquatic organisms, amphibians, mammalia and exposed humans. The overall evaluation is quite complex. Mercury compounds failed to induce point mutations in bacteria but often exerted clastogenic effects in eukaryotes, especially by binding SH groups and acting as spindle inhibitors, thereby causing c-mitosis and consequently aneuploidy and/or polyploidy. Inorganic mercury compounds were also found to induce the generation of reactive oxygen species and glutathione depletion in cultured mammalian cells. Although different mercury compounds tended to produce qualitatively comparable genetic effects, which suggests the involvement of a common toxic entity, methylmercury derivatives and other ionizable organomercury compounds were more active in short-term tests than either non-ionizable mercury compounds (e.g., dimethylmercury) or inorganic mercury salts (e.g., mercuric chloride). The results of cytogenetic monitoring in peripheral blood lymphocytes of individuals exposed to elemental mercury or mercury compounds from accidental, occupational or alimentary sources were either negative or borderline or uncertain as to the actual role played by mercury in some positive findings. Both genotoxic and non-genotoxic mechanisms may contribute to the renal carcinogenicity of mercury, which so far has been convincingly demonstrated only in male rodents treated with methylmercury chloride.
Assuntos
Compostos de Mercúrio/toxicidade , Mutagênicos/toxicidade , Animais , HumanosRESUMO
Specimens of rainbow trout (Oncorhynchus mykiss) were either kept in an aquarium under laboratory conditions or caged in the River Po (Northern Italy), upstream or downstream the confluence with the River Lambro, a small yet heavily polluted tributary. Genotoxicity biomarkers, evaluating the internal dose or early biological effects, were monitored after 7, 15 and 30 days of in situ exposure. With the exception of a slight increase of aminopyrine-N-demethylase and uridine-5'-diphospho-glucuronosyl-transferase, no significant effect was produced in fish kept upstream the River Lambro, as compared to control fish kept in the aquarium. In contrast, the responsibility of this tributary in carrying sublethal doses of both genotoxic agents and enzyme inducers into the main river was proved by the significant occurrence of early biological alterations in fish caged downstream. In fact, (a) bile extracts contained frameshift mutagens requiring metabolic activation, with a prevalence of liposoluble components after a short exposure, followed by a time-related increase of conjugated components, in minor part with glucuronic acid; (b) the monooxygenases aminopyrine-N-demethylase, uridine-5'-diphospho-glucuronosyl-transferase and, with sharp differences, arylhydrocarbon hydroxylase and 7-ethoxyresorufin-O-deethylase were enhanced in liver microsomal fractions; (c) the liver cytosolic fractions had an enhanced ability to convert 3-amino-1-methyl-5H-pyrido(4,3)indole into mutagenic metabolites in S. typhimurium; (d) cytogenetic damage was demonstrated by an increased frequency of micronuclei in peripheral blood erythrocytes.
Assuntos
Biomarcadores , Testes de Mutagenicidade , Mutagênicos/toxicidade , Poluição da Água , Animais , Benzo(a)pireno/farmacologia , Bile , Biotransformação , Carbolinas/metabolismo , Indução Enzimática , Eritrócitos/efeitos dos fármacos , Eritrócitos/ultraestrutura , Fígado/enzimologia , Testes para Micronúcleos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Mutagênicos/metabolismo , Oncorhynchus mykiss , Ratos , Ratos Sprague-Dawley , Esteroide Hidroxilases/biossínteseAssuntos
Anticarcinógenos/uso terapêutico , Antimutagênicos/uso terapêutico , Mutação , Neoplasias/prevenção & controle , Prevenção Primária , Animais , Anticarcinógenos/farmacologia , Antimutagênicos/farmacologia , Divisão Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Neoplasias/patologiaRESUMO
The induction in fish liver of some enzyme activities, and typically of microsomal mixed-function oxidases (MFO), provides the earliest biological warning signal of exposure to pollutants. Our studies provided evidence that the basal levels of cytochrome P-450 and specific MFO activities, such as arylhydrocarbon hydroxylase (AHH) and ethoxyresorufin deethylase (EROD), were strongly influenced by the diet in freshwater fish (Oncorhynchus mykiss). The response of fish liver to a known enzyme inducer, i.e., beta-naphthoflavone, was also affected by the diet, which therefore should be carefully controlled in laboratory studies. Under field conditions MFO activities were significantly enhanced in the liver of O. mykiss kept in polluted river water as well as in the liver of the seawater fish Diplodus annularis collected from a polluted harbour area, as compared to specimens of the same species collected from an unpolluted reference area.
Assuntos
Bioensaio/métodos , Monitoramento Ambiental , Peixes/metabolismo , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/biossíntese , Poluição da Água , Ração Animal , Animais , Benzoflavonas/farmacologia , Indução Enzimática/efeitos dos fármacos , Privação de Alimentos , Água Doce , Microssomos Hepáticos/efeitos dos fármacos , Salmão/metabolismo , Água do Mar , Especificidade da Espécie , beta-NaftoflavonaRESUMO
Male Sprague-Dawley rats were exposed whole-body to the mainstream smoke produced by a commercial filter cigarette for 8 consecutive days, accounting for a cumulative exposure to the smoke of 75 cigarettes. Liver and lung S12 fractions were used in the Salmonella mutagenicity test in order to assess either the decrease of potency of a direct-acting mutagen (sodium dichromate) or the metabolic activation of promutagens, including cigarette smoke itself and its condensate, benzo[a]pyrene and its 7,8-diol, the aromatic amine 2-aminofluorene, and the heterocyclic amine 3-amino-1-methyl-5H-pyrido(4,3)indole. Moreover, individual biochemical parameters were measured in the liver and lung of the same rats and, in the case of cytochrome P-450-dependent monooxygenases, also in the heart of untreated or Aroclor-treated rats. The monitored biochemical parameters included aryl hydrocarbon (benzo[a]pyrene) hydroxylase and ethoxyresorufin deethylase in microsomal fractions, epoxide (benzo[a]pyrene-4,5-oxide) hydrolase in both microsomal and cytosolic fractions, glutathione (GSH) and GSH S-transferase in the cytosol. Exposure to cigarette smoke resulted in a number of significant metabolic changes, as compared to sham-exposed rats. The most pronounced alterations consisted in a 2.6-fold induction of aryl hydrocarbon hydroxylase in the lung and 8-fold induction of ethoxyresorufin deethylase in the liver, and in a marked stimulation of the liver metabolic activation of all promutagens. The last effect was inhibited by the oral administration of the chemopreventive agent N-acetylcysteine. On the whole, there was a poor correlation between the monitored biochemical and mutagenicity endpoints.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Acetilcisteína/administração & dosagem , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nicotiana , Plantas Tóxicas , Fumaça/efeitos adversos , Administração Oral , Animais , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Testes de Mutagenicidade/métodos , Mutagênicos/metabolismo , Ratos , Ratos Endogâmicos , Salmonella typhimurium/genéticaRESUMO
The light emitted by halogen lamps induced mutations in Salmonella typhimurium and DNA damage in Escherichia coli, as shown by the hypersensitivity of DNA repair-deficient strains. The mutagenicity of halogen lamps was considerably higher than that of fluorescent light and of sunlight, even at much lower illuminance levels. Excision mechanisms and SOS functions were involved in repairing light-induced base-pair substitutions and frameshift errors in bacterial DNA. At variance with solar irradiation, which produces mutagenic effects over a wide UV spectrum, genotoxicity of halogen lamps was almost exclusively due to far-UV wavelengths transmissible through UV-R-250 and UV-R-280 interference filters. The main mutagenic component of fluorescent light (254 nm) were almost 10(4)-fold more mutagenic than near-UV wavelengths (365 nm). All light sources exhibited some residual mutagenicity even following filtration through various cloths. On the other hand, appropriate glass or plastic covers consistently prevented mutagenic effects. This emphasizes the urgent need for a compulsory shielding of halogen and fluorescent lamps in order to prevent unnecessary exposures to genotoxic and potentially carcinogenic UV radiations.
Assuntos
Dano ao DNA , Iluminação/efeitos adversos , Escherichia coli/efeitos da radiação , Luz/efeitos adversos , Testes de Mutagenicidade , Salmonella typhimurium/efeitos da radiação , Raios Ultravioleta/efeitos adversosRESUMO
The mono-electronic reduction of oxygen in the hypoxanthine-xanthine oxidase system led to the formation of active species eliciting an evident and highly reproducible mutagenic response in strain TA104 of S. typhimurium. Similar effects were observed by generating oxy radicals either extracellularly or inside bacterial cells. Mutagenicity was selectively detected in TA104 and not in other Salmonella strains, which points out the importance of the hisG428 mutation and of the deletion excising the uvrB gene, as far as sensitivity to oxy radicals is concerned. The mutagenicity of the system was further enhanced in the presence of superoxide dismutase. Catalase did not affect the mutagenicity of hypoxanthine plus xanthine oxidase, whereas it inhibited the mutagenicity induced by the mixture of hypoxanthine with xanthine oxidase and superoxide dismutase. This demonstrates that not only hydrogen peroxide but also the superoxide radical anion is positive in this system. Glutathione and 2 synthetic thiols, i.e., N-acetylcysteine and alpha-mercaptopropionylglycine, besides decreasing the high spontaneous mutagenicity of TA104, efficiently prevented the mutagenicity of active oxygen species.