RESUMEN
Photooxidative removal of pharmaceuticals and organic dyes is an effective way to eliminate growing micropollutants. However, photooxidation often results in byproducts as secondary hazardous substances such as phytotoxins. Herein, we found that photooxidation of common antibiotic tetracycline hydrochloride (TCH) over a metal-free 8-hydroxyquinoline (8-HQ) functionalized carbon nitride (CN) photocatalyst significantly reduces the TCH phytotoxic effect. The phytotoxicity test of photocatalytic treated TCH-solution evaluated towards seed growth of Cicer arietinum plant model endowed natural root and shoot growth. This study highlights the conceptual insights in designing of metal-free photocatalyst for environmental remediation.
Asunto(s)
Oxiquinolina , Tetraciclina , Tetraciclina/toxicidad , Oxiquinolina/toxicidad , Nitrilos/toxicidad , Antibacterianos/toxicidad , MetalesRESUMEN
Oxine-copper (OxCu) is generally used as an agricultural pesticide and induces harmful effects on ecosystems. In this study, zebrafish was used to assess the aquatic toxicity of OxCu. To detect the effects on development, embryos of 6 h post-fertilization (hpf) were exposed to 10 µg/L, 20 µg/L, 40 µg/L OxCu for 18 h; meanwhile, to evaluate the effects on the behavior, larval fish at 6 days post-fertilization (dpf) were exposed to the same concentrations for 24 h. Here, we show that there are embryonic developmental defects, including abnormalities of head and trunk, brain ventricle atrophy, reduced newborn neurons, disordered neurons, increased intercellular space, concentrated cytoplasm, decreased heart beat and blood flow velocity, and developmental delay of the vascular system; in addition, some embryos exposed to the high concentration of OxCu degraded from the tail. We also found that the spontaneous tail coiling frequency and AChE enzyme activity were reduced, while oxidative stress (free radical damage) and cell apoptosis were significantly increased. Moreover, the expression of genes involved in neurodevelopment, vascular development and apoptosis were dysregulated in the OxCu exposed embryos in a concentration-dependent manner. Finally, we found that after exposure to OxCu, larval locomotor activity was decreased and accompanied by Parkinson-like (increased absolute turn angle and sinuosity) and anxiety-like (preferred to the central area) behavior. These results indicate that OxCu induces developmental toxicity and behavioral alterations by affecting AChE enzyme activity and oxidative stress. Our data present new proofs of OxCu toxicity and a warning for its application.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cobre/toxicidad , Embrión no Mamífero/efectos de los fármacos , Larva/efectos de los fármacos , Oxiquinolina/toxicidad , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/crecimiento & desarrollo , Animales , Relación Dosis-Respuesta a Droga , Embrión no Mamífero/fisiología , Desarrollo Embrionario/efectos de los fármacos , Larva/fisiología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells-a hallmark feature of AAHC-by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.
Asunto(s)
Enterocolitis Seudomembranosa/genética , Enterotoxinas/metabolismo , Interacciones Microbiota-Huesped/genética , Klebsiella oxytoca/genética , Animales , Benzodiazepinonas/metabolismo , Benzodiazepinonas/toxicidad , Daño del ADN/efectos de los fármacos , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/patología , Enterotoxinas/biosíntesis , Células Epiteliales/microbiología , Células Epiteliales/patología , Humanos , Intestinos/microbiología , Intestinos/patología , Infecciones por Klebsiella/genética , Infecciones por Klebsiella/microbiología , Klebsiella oxytoca/metabolismo , Klebsiella oxytoca/patogenicidad , Ratones , Microtúbulos/efectos de los fármacos , Oxiquinolina/análogos & derivados , Oxiquinolina/metabolismo , Oxiquinolina/toxicidad , Péptidos/metabolismo , Péptidos/toxicidadRESUMEN
The development of new therapeutic strategies to treat leishmaniasis has become a priority. In the present study, the antileishmanial activity of 8-hydroxyquinoline (8-HQN) was investigated against in vitro promastigotes and in vivo intra-macrophage amastigotes of three Leishmania species: Leishmania amazonensis, Leishmania infantum and Leishmania braziliensis. Studies were performed to establish the 50% Leishmania inhibitory concentration (IC50) of 8-HQN, as well as its 50% cytotoxic concentration (CC50) on murine macrophages and in human red blood cells. The inhibition of macrophages infection was also evaluated using parasites that were pre-treated with 8-HQN. The effects of this compound on nitric oxide (NO) production and in the mitochondrial membrane potential were also evaluated. Finally, the therapeutic efficacy of 8-HQN was assessed in a known murine model, L. amazonensis-chronically infected BALB/c mice. Our results showed that 8-HQN was effective against promastigote and amastigote stages of all tested Leishmania species, presenting a selectivity index of 328.0, 62.0 and 47.0 for L. amazonensis, L. infantum and L. braziliensis, respectively. It was effective in treating infected macrophages, as well as in preventing the infection of these cells using pre-treated parasites. In addition, 8-HQN caused an alteration in the mitochondrial membrane potential of the parasites. When administered at 10mg/kg body weight/day by subcutaneous route, this product was effective in reducing the lesion diameter, as well as the parasite load in evaluated tissues and organs of infected animals. The results showed the in vitro and in vivo efficacy of 8-HQN against three different Leishmania species causing tegumentary and/or visceral leishmaniasis, and it could well be used for future therapeutic optimization studies to treat leishmaniasis.
Asunto(s)
Leishmania infantum/efectos de los fármacos , Leishmania/efectos de los fármacos , Oxiquinolina/farmacología , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/toxicidad , Eritrocitos/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Leishmania braziliensis/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Visceral/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Oxiquinolina/uso terapéutico , Oxiquinolina/toxicidad , Carga de Parásitos , Resultado del TratamientoRESUMEN
We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and ß-amyloid (Aß)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Aß self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1 b), 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (2 b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3 a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity inâ vitro. Importantly, in the case of 2 b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Oxiquinolina/química , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/uso terapéutico , Antioxidantes/toxicidad , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quelantes/química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/toxicidad , Clioquinol/química , Clioquinol/uso terapéutico , Clioquinol/toxicidad , Cobre/química , Donepezilo , Diseño de Fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Indanos/química , Indanos/uso terapéutico , Indanos/toxicidad , Oxiquinolina/uso terapéutico , Oxiquinolina/toxicidad , Piperidinas/química , Piperidinas/uso terapéutico , Piperidinas/toxicidad , Relación Estructura-Actividad , Zinc/químicaRESUMEN
To evaluate the environmental toxicity of 8-hydroxyquinoline (8-HOQ), an important industrial raw material found in China's major ornamental fish, Cryprinus carpio, using the acute toxicity test, hepatase activity analysis and the comet assay. The results indicated that 8-HOQ had significant acute toxicity in adult C. carpio with a 96 h-LC50 of 1.15 and 0.22 mg L(-1) hepatic quinoline residues as assessed by HPLC. 8-HOQ also induced genotoxicity in the form of strand breaks in the DNA of hepatic cells as shown by the comet assay. With regard to physiological toxicity, 8-HOQ induced a decrease in the activities of hepatic GOT and GPT with increased exposure concentration and time. These data suggest that 8-HOQ may be toxic to the health of aquatic organisms when accidentally released into aquatic ecosystems. The data also suggest that the comet assay may be used in biomonitoring to determine 8-HOQ genotoxicity and hepatic GPT and GOT activities may be potential biomarkers of physiological toxicity.
Asunto(s)
Carpas/metabolismo , Oxiquinolina/toxicidad , Plaguicidas/toxicidad , Pruebas de Toxicidad Aguda , Contaminantes Químicos del Agua/toxicidad , Animales , China , Cromatografía Líquida de Alta Presión , Ensayo Cometa , Daño del ADN/efectos de los fármacos , Monitoreo del Ambiente/métodosRESUMEN
In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. The radiation-induced cell death of normal cells is caused, at least in part, by apoptosis, which undergoes via activation of p53 and increase in the p53 protein, a zinc-containing transcriptional factor, in response to cellular damage. Therefore, radioprotective drugs that can protect normal cells from radiation and thus suppress adverse side effects would be highly desirable. We report herein on the radioprotective activity of 8-hydroxyquinoline (8HQ) derivatives that were initially designed so as to interact with the Zn(2+) in p53. Indeed, the 5,7-bis(methylaminosulfonyl)-8HQ and 8-methoxyquinoline derivatives considerably protected MOLT-4 cells against γ-ray radiation (10 Gy), accompanied by a low cytotoxicity. However, mechanistic studies revealed that the interaction of these drugs with p53 is weak and the mechanism for inhibiting apoptosis appears to be different from that of previously reported radioprotectors such as bispicen, which inhibits apoptosis via the denaturation of p53 as well as by blocking both transcription-dependent and -independent apoptotic pathways.
Asunto(s)
Diseño de Fármacos , Oxiquinolina/química , Protectores contra Radiación/síntesis química , Zinc/química , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Ensayo de Cambio de Movilidad Electroforética , Rayos gamma , Humanos , Oxiquinolina/síntesis química , Oxiquinolina/toxicidad , Protectores contra Radiación/química , Protectores contra Radiación/toxicidad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
On the basis of an initial molecular modeling study suggesting the favorable binding of the "privileged" fragment 8-hydroxyquinoline with HIV-1 integrase (IN) at the IN-lens epithelium-derived growth factor/p75 (LEDGF/p75) interface , we developed a set of modified 8-hydroxyquinoline fragments demonstrating micromolar IC50 values for inhibition of the IN-LEDGF/p75 interaction, but significant cytotoxicity was associated with these initial compounds. Diverse modifications at the C5 and C7 carbons of the 8-hydroxyquinoline core improved potency, but reduction of diversity to only modifications at the C5 position ultimately yielded potent inhibitors with low cytotoxicity. Two of these particular compounds, 5-((p-tolylamino)methyl)quinolin-8-ol and 5-(((3,4-dimethylphenyl)amino)methyl)quinolin-8-ol, inhibited viral replication in MT-4 cells with low micromolar EC50. This is the first study providing evidence for 8-hydroxyquinolines as novel inhibitors of the IN-LEDGF/p75 interaction. Our lead compounds are druglike, have low molecular weights, and are amenable to various substitutions suitable for enhancing their potency and selectivity.
Asunto(s)
Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , Integrasa de VIH/metabolismo , VIH-1/enzimología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Oxiquinolina/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/toxicidad , Línea Celular , Integrasa de VIH/química , VIH-1/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Oxiquinolina/química , Oxiquinolina/toxicidad , Piperazina , Piperazinas/química , Piperidinas/química , Unión Proteica/efectos de los fármacos , Conformación Proteica , Relación Estructura-ActividadRESUMEN
This study was a preliminary step in evaluating the genotoxic effects of 8-hydroxylquinoline (8-HOQ) in loach (Misgurnus anguillicaudatus) using the micronucleus, comet and RAPD assays. In the micronucleus test and comet assay, the micronuclei rate (%) and three comet parameters (trailing rate, tail length and tail moment) in treated fish increased with increasing 8-HOQ concentration and treatment time. These results showed that exposure to 8-HOQ significantly induced genetic toxicity in loach blood cells. A subsequent RAPD assay also showed that 8-HOQ induced a genotoxic effect in loach. Among the 23 tested RAPD primers, 11 primers produced unique polymorphic band patterns and generated RAPD profile variations that displayed the band intensity, disappearance of bands and appearance of new bands of amplified DNA in the 8-HOQ-treated genomic DNA samples. In addition, the variation in RAPD profiles was time- and concentration-dependent. These results suggested that 8-HOQ is potentially harmful to fish and may be a toxic contaminant in the aquatic environment.
Asunto(s)
Cipriniformes , Mutágenos/toxicidad , Oxiquinolina/toxicidad , Plaguicidas/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Ensayo Cometa , Daño del ADN , Dosificación Letal Mediana , Micronúcleos con Defecto Cromosómico , Pruebas de Micronúcleos , Técnica del ADN Polimorfo Amplificado AleatorioRESUMEN
OBJECTIVES: To determine the effect of 8-hydroxyquinoline (8HQ) on non-replicating Mycobacterium tuberculosis (Mtb) in comparison with its reported effect on replicating Mtb. METHODS: The MIC of 8HQ for replicating H37Rv Mtb was determined by microdilution in 7H9 broth. Bactericidal activity was determined by exposing H37Rv Mtb to 8HQ for 4 days under conditions that otherwise allowed exponential replication (20% O(2), pH 6.6) and conditions under which replication was precluded: 1% O(2), pH 6.6; 20% O(2), pH 5.5; or 20% O(2), pH 5.5, 0.5 mM sodium nitrite. Serial dilutions were plated on 7H11 agar to quantify cfu. Frequency of resistance (FOR) was determined with >10(9) bacteria plated on 7H9 agar plates containing 2x MIC 8HQ. RESULTS: 8HQ was active against replicating Mtb (MIC 2.5 microM, 0.36 mg/L). Under both replicating and non-replicating conditions, cfu were reduced in 4 days by > or = 5 log(10) at the highest concentration tested (10 microM). Bactericidal activity was maximal at low pH, where 8HQ reduced cfu by 1-1.5 log(10) at 1 microM. We were unable to recover any 8HQ-resistant colonies. CONCLUSIONS: This study demonstrates that 8HQ has bactericidal activity of comparable potency against non-replicating and replicating Mtb, a property not observed for anti-infective agents currently approved for treatment of tuberculosis, and a very low FOR. Drugs with these properties are urgently needed to shorten the course of treatment for both active and latent tuberculosis.
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Antituberculosos/farmacología , Viabilidad Microbiana/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Oxiquinolina/farmacología , Animales , Antituberculosos/toxicidad , Chlorocebus aethiops , Recuento de Colonia Microbiana , Farmacorresistencia Bacteriana , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Oxiquinolina/toxicidad , Células VeroRESUMEN
An extract of roots of Centaurea diffusa (diffuse knapweed) yielded caryophyllene oxide and linoleic acid which were shown to be phytotoxic. Also isolated were germacrene B, a previously-known phytotoxin as well as the inactive polyene aplotaxene. A combination of these compounds, if transferred to the soil, could be one factor in the invasive behavior of this weed. Contrary to a literature report, 8-hydroxyquinoline was not detected in root exudates of in vitro grown C. diffusa nor could it be identified in the root extract. However, a recent report from a different group maintains that 8-hydroxyquinoline can be released from roots of C. diffusa following a diurnal rhythm.
Asunto(s)
Centaurea/metabolismo , Raíces de Plantas/metabolismo , Arabidopsis/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Ácido Linoleico/metabolismo , Ácido Linoleico/toxicidad , Oxiquinolina/metabolismo , Oxiquinolina/toxicidad , Sesquiterpenos Policíclicos , Plantones/efectos de los fármacos , Sesquiterpenos/metabolismo , Sesquiterpenos/toxicidad , Sesquiterpenos de Germacrano/metabolismo , Sesquiterpenos de Germacrano/toxicidadRESUMEN
BACKGROUND: Radioactive labeling with indium (In) tracers has been among the most widely used methods for tracking stem cells. As the first experiment on human stem cells, we designed a study to continuously follow the influence of In labeling on stem cell viability during the 2-week period of postlabeling. METHODS: After culturing mesenchymal stem cells (MSCs), we divided the cells into six samples, each of which contained 1x10 MSCs. The first sample was considered as the control. The remaining five samples (samples 2-6) were labeled with the following doses of In-oxine, respectively: 0.76, 1.64, 3.48, 5.33, and 7.16 MBq/10 MSCs. To evaluate the effects of In-oxine labeling on cellular viability and count, all samples were examined immediately after labeling (2 h) as well as 24, 48 h, and 5, 7, and 14 days postlabeling. RESULTS: No statistically significant relationship was found between labeling efficiency and administered dose. Associations between the specific activity and radiotracer dosage was significant (P=0.001, r=0.9). In addition, a negative correlation was noted between radiotracer dosage and viability during the 2-week period of follow-up. CONCLUSION: Cytotoxic effects of In on human stem cells is a time-dependent phenomenon and hence, assessment of the stem cell viability immediately after labeling (which is frequently made in clinical trials) is unable to detect adverse effects of this radiopharmaceutical on the integrity of stem cells. Even low doses of In-oxine are accompanied by significant cell loss in a 2-week period. Although it has been confirmed that nuclear medicine techniques are the most sensitive methods for stem cell tracking, we recommend that the application of this tracking technique should be treated with great reserve, and if necessary, as little of In-oxine as possible should be added to the cells (or only a limited portion of the cells should be labeled) to minimize cell death.
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Células Madre Mesenquimatosas/efectos de la radiación , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/toxicidad , Oxiquinolina/análogos & derivados , Animales , Recuento de Células , Supervivencia Celular/efectos de la radiación , Perros , Humanos , Células Madre Mesenquimatosas/citología , Oxiquinolina/efectos adversos , Oxiquinolina/toxicidad , Dosis de Radiación , Ratas , Factores de TiempoRESUMEN
A transgenic tobacco overexpressing ferritin (P6) was recently shown to accumulate more iron than the wild type (WT), leading to a reduced availability of iron in the rhizosphere and shifts in the pseudomonad community. The impact of the transgenic line on the community of fluorescent pseudomonads was assessed. The diversity of 635 isolates from rhizosphere soils, rhizoplane + root tissues, and root tissues of WT and P6, and that of 98 isolates from uncultivated soil was characterized. Their ability to grow under iron stress conditions was assessed by identifying their minimal inhibitory concentrations of 8-hydroxyquinoline for each isolate, pyoverdine diversity by isoelectrofocusing and genotypic diversity by random amplified polymorphism DNA. The antagonistic activity of representative isolates and of some purified pyoverdines against a plant pathogen (Pythium aphanidermatum Op4) was tested in vitro. In overall, isolates taken from P6 tobacco showed a greater ability to grow in iron stress conditions than WT isolates. The antagonism by some of the representative isolates was only expressed under iron stress conditions promoting siderophore synthesis and their pyoverdines appeared to have a specific structure as assessed by mass spectrometry. For other isolates, antagonism was still expressed in the presence of iron, suggesting the involvement of metabolites other than siderophores. Altogether, these data indicate that the transgenic tobacco that over-accumulates iron selected fluorescent pseudomonads, less susceptible to iron depletion and more antagonistic to the tested plant pathogen than those selected by the tobacco WT.
Asunto(s)
Biodiversidad , Ferritinas/metabolismo , Hierro/metabolismo , Nicotiana/microbiología , Raíces de Plantas/microbiología , Pseudomonas/metabolismo , Focalización Isoeléctrica , Pruebas de Sensibilidad Microbiana , Oligopéptidos/metabolismo , Oxiquinolina/toxicidad , Filogenia , Plantas Modificadas Genéticamente , Pseudomonas/efectos de los fármacos , Pseudomonas/genética , Pythium , Técnica del ADN Polimorfo Amplificado Aleatorio , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Nicotiana/metabolismoRESUMEN
Tris(8-quinolinolato-N1, O8) aluminum (AlQ), an aluminum chelate of 8-hydroxyquinoline (8OHQ) is an important charge transfer molecule in semiconducting imaging devices. This study was conducted to evaluate AlQ and 8OHQ for the ability to induce reverse mutations, either in the presence or absence of mammalian microsomal enzymes, and to determine if AlQ decomposes or is metabolized to 8OHQ under assay conditions. The tester strains used in the mutation assay were Salmonella typhimurium TA98, TA100, TA1535 and TA1537 and Escherichia coli WP2uvrA (pKM101). The assays were conducted in the presence and absence of S9. AlQ doses were 1-1000 microg per plate while 8OHQ doses were 0.947-947 microg per plate to maintain molar equivalency. Stability studies were carried out for 4h at 37 degrees C under conditions designed to mimic mutation assays. Samples were analyzed by HPLC and LC/MS to tentatively identify potential metabolites of AlQ and 8OHQ. The results of the bacterial mutagenicity assay indicate that in the presence of S9, both AlQ and 8OHQ, caused increases in the mean number of revertants per plate with tester strains TA100 and WP2uvrA (pKM101). No increases were observed with any of the remaining tester strain/activation condition combinations. The stability study showed that AlQ degrades readily to 8OHQ under standard mutagenicity test conditions, and the positive test result with AlQ is due to the bioactivation of 8OHQ. In the presence of S9, 8OHQ is metabolized to one detectable product with molecular weight indicative of a one-oxygen insertion. 8OHQ N-oxide and 2,8-quinolinediol were ruled out as possible metabolites; 8OHQ epoxides and other quinolinediols were neither confirmed nor ruled out. Bacterial mutagenicity tests have not been shown to predict in vivo effects of 8OHQ; these assays are similarly expected to be poorly predictive of in vivo genotoxic and carcinogenic potential of AlQ.
Asunto(s)
Escherichia coli/efectos de los fármacos , Mutación , Compuestos Organometálicos/química , Oxiquinolina/toxicidad , Salmonella typhimurium/efectos de los fármacos , Animales , Escherichia coli/genética , Masculino , Pruebas de Mutagenicidad , Oxiquinolina/síntesis química , Ratas , Ratas Sprague-Dawley , Salmonella typhimurium/genéticaRESUMEN
In the current study we present a view of events leading to chemically induced DNA damage in vitro from both a cytogenetic and molecular aspect, focusing on threshold mediated responses and the biological relevance of DNA damaging events that occur at low and high cellular toxicity levels. Current regulatory mechanisms do not take into account chemicals that cause significant DNA damage only at high toxicity. Our results demonstrate a defined threshold for micronucleus induction after insult with the alkylating agent MMS. Other results define a significant change in gene expression following treatment with chemicals that give rise to structural DNA damage only at high toxicity. Pairs of chemicals with a similar mode of action but differing toxicity levels were chosen, the chemicals that demonstrated structural DNA damage only at high levels of toxicity showed an increase in heat shock protein gene expression whereas the chemicals causing DNA damage events at all levels of toxicity did not induce changes in heat shock gene expression at identical toxicity levels. The data presented indicates that there are a number of situations where the linear dose response model is not appropriate for risk estimation. However, deviation from linear risk models should be dependent upon the availability of appropriate experimental data such as that shown here.
Asunto(s)
Aneuploidia , Aberraciones Cromosómicas , Perfilación de la Expresión Génica , Mutágenos/toxicidad , Alquilantes/farmacología , Alquilantes/toxicidad , Amsacrina/farmacología , Amsacrina/toxicidad , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Cromosomas Humanos/efectos de los fármacos , Cromosomas Humanos/ultraestructura , Citocalasina B/farmacología , Daño del ADN , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Etopósido/farmacología , Etopósido/toxicidad , Guanina/análogos & derivados , Guanina/análisis , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/ultraestructura , Metilmetanosulfonato/farmacología , Metilmetanosulfonato/toxicidad , Pruebas de Micronúcleos , Oxiquinolina/farmacología , Oxiquinolina/toxicidad , Riesgo , Inhibidores de Topoisomerasa IIRESUMEN
The sensitivity responses of seven pso mutants of Saccharomyces cerevisiae towards the mutagens N-nitrosodiethylamine (NDEA), 1,2:7,8-diepoxyoctane (DEO), and 8-hydroxyquinoline (8HQ) further substantiated their allocation into two distinct groups: genes PSO1 (allelic to REV3), PSO2 (SNM1), PSO4 (PRP19), and PSO5 (RAD16) constitute one group in that they are involved in repair of damaged DNA or in RNA processing whereas genes PSO6 (ERG3) and PSO7 (COX11) are related to metabolic steps protecting from oxidative stress and thus form a second group, not responsible for DNA repair. PSO3 has not yet been molecularly characterized but its pleiotropic phenotype would allow its integration into either group. The first three PSO genes of the DNA repair group and PSO3, apart from being sensitive to photo-activated psoralens, have another common phenotype: they are also involved in error-prone DNA repair. While all mutants of the DNA repair group and pso3 were sensitive to DEO and NDEA the pso6 mutant revealed WT or near WT resistance to these mutagens. As expected, the repair-proficient pso7-1 and cox11-Delta mutant alleles conferred high sensitivity to NDEA, a chemical known to be metabolized via redox cycling that yields hydroxylamine radicals and reactive oxygen species. All pso mutants exhibited some sensitivity to 8HQ and again pso7-1 and cox11-Delta conferred the highest sensitivity to this drug. Double mutant snm1-Delta cox11-Delta exhibited additivity of 8HQ and NDEA sensitivities of the single mutants, indicating that two different repair/recovery systems are involved in survival. DEO sensitivity of the double mutant was equal or less than that of the single snm1-Delta mutant. In order to determine if there was oxidative damage to nucleotide bases by these drugs we employed an established bacterial test with and without metabolic activation. After S9-mix biotransformation, NDEA and to a lesser extent 8HQ, lead to significantly higher mutagenesis in an Escherichia coli tester strain WP2-IC203 as compared to WP2, whereas DEO-induced mutagenicity remained unchanged
Asunto(s)
ADN de Hongos/genética , Estrés Oxidativo/genética , Mutágenos/toxicidad , Reparación del ADN/genética , Saccharomyces cerevisiae/genética , Compuestos Epoxi/toxicidad , ADN de Hongos/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Dietilnitrosamina/toxicidad , Genes Fúngicos , Oxiquinolina/toxicidad , Fenotipo , Proteínas de Saccharomyces cerevisiae/efectos de los fármacos , Proteínas de Saccharomyces cerevisiae/genética , Reparación del ADN/efectos de los fármacos , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/efectos de los fármacosRESUMEN
The sensitivity responses of seven pso mutants of Saccharomyces cerevisiae towards the mutagens N-nitrosodiethylamine (NDEA), 1,2:7,8-diepoxyoctane (DEO), and 8-hydroxyquinoline (8HQ) further substantiated their allocation into two distinct groups: genes PSO1 (allelic to REV3), PSO2 (SNM1), PSO4 (PRP19), and PSO5 (RAD16) constitute one group in that they are involved in repair of damaged DNA or in RNA processing whereas genes PSO6 (ERG3) and PSO7 (COX11) are related to metabolic steps protecting from oxidative stress and thus form a second group, not responsible for DNA repair. PSO3 has not yet been molecularly characterized but its pleiotropic phenotype would allow its integration into either group. The first three PSO genes of the DNA repair group and PSO3, apart from being sensitive to photo-activated psoralens, have another common phenotype: they are also involved in error-prone DNA repair. While all mutants of the DNA repair group and pso3 were sensitive to DEO and NDEA the pso6 mutant revealed WT or near WT resistance to these mutagens. As expected, the repair-proficient pso7-1 and cox11-Delta mutant alleles conferred high sensitivity to NDEA, a chemical known to be metabolized via redox cycling that yields hydroxylamine radicals and reactive oxygen species. All pso mutants exhibited some sensitivity to 8HQ and again pso7-1 and cox11-Delta conferred the highest sensitivity to this drug. Double mutant snm1-Delta cox11-Delta exhibited additivity of 8HQ and NDEA sensitivities of the single mutants, indicating that two different repair/recovery systems are involved in survival. DEO sensitivity of the double mutant was equal or less than that of the single snm1-Delta mutant. In order to determine if there was oxidative damage to nucleotide bases by these drugs we employed an established bacterial test with and without metabolic activation. After S9-mix biotransformation, NDEA and to a lesser extent 8HQ, lead to significantly higher mutagenesis in an Escherichia coli tester strain WP2-IC203 as compared to WP2, whereas DEO-induced mutagenicity remained unchanged.
Asunto(s)
Reparación del ADN/genética , ADN de Hongos/genética , Mutágenos/toxicidad , Estrés Oxidativo/genética , Saccharomyces cerevisiae/genética , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Reparación del ADN/efectos de los fármacos , ADN de Hongos/efectos de los fármacos , Dietilnitrosamina/toxicidad , Compuestos Epoxi/toxicidad , Genes Fúngicos , Oxiquinolina/toxicidad , Fenotipo , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/efectos de los fármacos , Proteínas de Saccharomyces cerevisiae/efectos de los fármacos , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
This study demonstrates that cupric 8-quinolinoxide (CuQ) has induced genetic toxicity in bacteria and mammalian cells through a mechanism of reactive oxygen species (ROS) generation. In the Ames test with rat liver S9, CuQ dose-dependently caused a point mutation in Salmonella typhimurium TA100. The effect of CuQ on DNA damage in HL60 and V79 cells identified in the comet assay is direct and enhanced by the addition of S9. Meanwhile, the tailing length of comet DNA is related to the increasing dosage of CuQ. The genotoxic effect of CuQ on either gene mutation in bacteria or DNA damage in culture cells can be generally blocked by several antioxidants, e.g. pyrrolidinedithiocarbamate, N-acetylcysteine, Vitamins C and E. Supportive of this observation, ROS generation induced by CuQ can be demonstrated both in vitro and in vivo by using the DCFH-DA fluoroprobe. The CuQ-induced intracellular ROS level is also dramatically inhibited by the above antioxidants. Above results imply that the CuQ-induced genotoxicity could be mediated by ROS generation. The nature of ferrous-dependent and S9-enhancing in CuQ-induced ROS generation hints a Fenton-like reaction or some specific enzymes activation could be involved in this process. Furthermore, a DNA damage- and oxidative stress-dependent protein, P53, could also been induced by CuQ treatments in a time-course and dose-dependent manners. Its expression level is recoverable by antioxidants too. In conclusion, our current study strongly suggests that CuQ induces gene mutation, global DNA damage, and P53 expression through a ROS-dependent mechanism.
Asunto(s)
Mutágenos/toxicidad , Compuestos Organometálicos/toxicidad , Oxiquinolina/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/farmacología , Biotransformación , Línea Celular , Ensayo Cometa , Cricetinae , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Oxiquinolina/análogos & derivados , Mutación Puntual , Ratas , Salmonella typhimurium/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The effects of two gallium (Ga) compounds, Ga chloride (GaCl3) and tris(8-quinolinolato)Ga (III) on the viability of A549 human malignant lung adenocarcinoma cells were investigated. The results demonstrated that both drugs reduced the viability of A549 cells but to different extents. The inhibitory effects of tris(8-quinolinolato)Ga (III) were 10 times more profound than those produced by GaCl3. The IC50 was obtained with 2.5 microM of tris(8-quinolinolato)Ga (III) and 25 microM GaCl3 after an exposure time of 48 hours. Further, whereas the inhibitory effects of GaCl3 were both dose and time-dependent those of tris(8-quinolinolato)Ga (III) appeared to be only dose-dependent, indicating differences in their mechanism of action. Comparison with data drawn from the literature suggests that GaCl3 seems to be in the same range of activity as Ga nitrate or Ga-pyridoxal isocotinoyl hydrazone. Tris(8-quinolinolato)Ga (III) could be as effective as transferrin-Ga, but with the advantage of oral administration and a greater bioavailability of the tris(8-quinolinolato)Ga (III) compound.
Asunto(s)
Antineoplásicos/toxicidad , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Galio/toxicidad , Compuestos Organometálicos/toxicidad , Oxiquinolina/análogos & derivados , Adenocarcinoma , Humanos , Cinética , Neoplasias Pulmonares , Oxiquinolina/toxicidad , Células Tumorales CultivadasRESUMEN
The potential cytotoxic effects of the compounds 8-quinolinol, chloramine-T and natamycin have been studied in isolated pig hepatocytes. The relative cytotoxicity of these compounds was evaluated on the basis of the leakage of cytosolic lactate dehydrogenase (LDH), 3-(4,5 dimethyl)thiazol-2-yl,-2,5-diphenyl tetrazolium bromide (MTT) reduction by mitochondrial dehydrogenases, uptake of neutral red (NR) by cytosolic lysosomes, glutathion (GSH) depletion and oxidized glutathion (GSSG) efflux after 24 h exposure. Evaluation of the 20%, 50% and 80% reduced absorbance data obtained from the parameters NR20, NR50, and NR80, and MTT20, MTT50 and MTT80 enabled us to rank these compounds in decreasing order of cytotoxicity: 8-quinolinol > natamycin > chloramine-T. Also for the parameters LDH and GSH, chloramine-T appears to be less cytotoxic than natamycin and 8-quinolinol. Our study demonstrated that pig hepatocytes may be a useful model for examining cytotoxic events of drugs to be used in pigs, therefore avoiding possible extrapolation problems due to species differences.