Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 18.202
Filtrar
Más filtros

Intervalo de año de publicación
1.
Chem Res Toxicol ; 37(2): 181-198, 2024 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-38316048

RESUMEN

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., ß-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure-activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.


Asunto(s)
Carcinógenos , Nitrosaminas , Humanos , Animales , Carcinógenos/toxicidad , Nitrosaminas/toxicidad , Nitrosaminas/metabolismo , Mutágenos/toxicidad , Roedores/metabolismo , Carcinogénesis , Carbono , Pruebas de Mutagenicidad
2.
Transfusion ; 64(6): 1097-1108, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38716879

RESUMEN

BACKGROUND: N-(-9 acridinyl)-b-alanine hydrochloride (S-300) is the main byproduct of red blood cell (RBC) amustaline/glutathione(GSH) pathogen reduction, currently undergoing phase III US clinical trials following successful European studies(1-3). Phosphatidylinositol glycan, class A (Pig-a) X-linked gene mutagenesis is a validated mammalian in vivo mutation assay for genotoxicity, assessed as clonal loss of glycosylphosphatidylinositol-linked CD59 cell-surface molecules on reticulocytes (RETs) and RBCs. METHODS: Male Sprague-Dawley rats received continuous infusion of S-300 up to the maximum feasible dose (240 mg/kg/day-limited by solubility and volume) for 28 days. Positive controls received a known mutagen by oral gavage on Days 1-3. Plasma levels of S-300 were assessed by HPLC before, during and after infusion. CD59-negative RBCs and RETs were enumerated in pre-dose and Day 28 samples, using a flow cytometric method. Outcome was evaluated by predetermined criteria using concurrent and historical controls. Toxicity was assessed by laboratory measures and necropsy. RESULTS: S-300 reached maximum, dose-dependent levels (3-15 µmol/L) within 2-8 h that were sustained for 672 h and undetectable 2 h after infusion. Circulating RET levels indicated a lack of hematopoietic toxicity. Necropsy revealed minimal-mild observations related to poor S-300 solubility at high concentrations. Pig-a assessment met the preset acceptability criteria and revealed no increase in mutant RBCs or RETs. CONCLUSIONS: Maximum feasible S-300 exposure of rats by continuous infusion for 28 days was not genotoxic as assessed by an Organization for Economic Cooperation and Development-compliant, mammalian, in vivo Pig-a gene mutation assay that meets the requirements of International Conference on Harmonization (ICH) S2(R1) and FDA guidances on genotoxicity testing.


Asunto(s)
Pruebas de Mutagenicidad , Ratas Sprague-Dawley , Animales , Masculino , Ratas , Pruebas de Mutagenicidad/métodos , Antígenos CD59/genética , Reticulocitos/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Proteínas de la Membrana/genética , Mutagénesis/efectos de los fármacos , Mutágenos/toxicidad
3.
Mutagenesis ; 39(2): 146-155, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38183270

RESUMEN

The two-test in vitro battery for genotoxicity testing (Ames and micronucleus) has in the majority of cases replaced the three-test battery (as two-test plus mammalian cell gene mutation assay) for the routine testing of chemicals, pharmaceuticals, cosmetics, and agrochemical metabolites originating from food and feed as well as from water treatment. The guidance for testing agrochemical groundwater metabolites, however, still relies on the three-test battery. Data collated in this study from 18 plant protection and related materials highlights the disparity between the often negative Ames and in vitro chromosome aberration data and frequently positive in vitro mammalian cell gene mutation assays. Sixteen of the 18 collated materials with complete datasets were Ames negative, and overall had negative outcomes in in vitro chromosome damage tests (weight of evidence from multiple tests). Mammalian cell gene mutation assays (HPRT and/or mouse lymphoma assay (MLA)) were positive in at least one test for every material with this data. Where both MLA and HPRT tests were performed on the same material, the HPRT seemed to give fewer positive responses. In vivo follow-up tests included combinations of comet assays, unscheduled DNA synthesis, and transgenic rodent gene mutation assays, all gave negative outcomes. The inclusion of mammalian cell gene mutation assays in a three-test battery for groundwater metabolites is therefore not justified and leads to unnecessary in vivo follow-up testing.


Asunto(s)
Hipoxantina Fosforribosiltransferasa , Linfoma , Ratones , Animales , Pruebas de Mutagenicidad , Ensayo Cometa , Roedores , Agroquímicos , Pruebas de Micronúcleos , Daño del ADN
4.
Mutagenesis ; 39(2): 69-77, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38301659

RESUMEN

Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo, this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing.


Asunto(s)
Carcinogénesis , Carcinógenos , Animales , Humanos , Carcinógenos/toxicidad , Pruebas de Carcinogenicidad/métodos , Pruebas de Mutagenicidad/métodos , Daño del ADN , Técnicas In Vitro
5.
Mutagenesis ; 39(2): 78-95, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38112628

RESUMEN

The robust control of genotoxic N-nitrosamine (NA) impurities is an important safety consideration for the pharmaceutical industry, especially considering recent drug product withdrawals. NAs belong to the 'cohort of concern' list of genotoxic impurities (ICH M7) because of the mutagenic and carcinogenic potency of this chemical class. In addition, regulatory concerns exist regarding the capacity of the Ames test to predict the carcinogenic potential of NAs because of historically discordant results. The reasons postulated to explain these discordant data generally point to aspects of Ames test study design. These include vehicle solvent choice, liver S9 species, bacterial strain, compound concentration, and use of pre-incubation versus plate incorporation methods. Many of these concerns have their roots in historical data generated prior to the harmonization of Ames test guidelines. Therefore, we investigated various Ames test assay parameters and used qualitative analysis and quantitative benchmark dose modelling to identify which combinations provided the most sensitive conditions in terms of mutagenic potency. Two alkyl-nitrosamines, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were studied. NDMA and NDEA mutagenicity was readily detected in the Ames test and key assay parameters were identified that contributed to assay sensitivity rankings. The pre-incubation method (30-min incubation), appropriate vehicle (water or methanol), and hamster-induced liver S9, alongside Salmonella typhimurium strains TA100 and TA1535 and Escherichia coli strain WP2uvrA(pKM101) provide the most sensitive combination of assay parameters in terms of NDMA and NDEA mutagenic potency in the Ames test. Using these parameters and further quantitative benchmark dose modelling, we show that N-nitrosomethylethylamine (NMEA) is positive in Ames test and therefore should no longer be considered a historically discordant NA. The results presented herein define a sensitive Ames test design that can be deployed for the assessment of NAs to support robust impurity qualifications.


Asunto(s)
Nitrosaminas , Humanos , Animales , Cricetinae , Nitrosaminas/toxicidad , Nitrosaminas/química , Mutágenos/toxicidad , Mutágenos/química , Dietilnitrosamina/toxicidad , Mutagénesis , Pruebas de Mutagenicidad/métodos , Carcinógenos/toxicidad
6.
Arch Microbiol ; 206(6): 262, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38753198

RESUMEN

The employment of versatile bacterial strains for the efficient degradation of carcinogenic textile dyes is a sustainable technology of bioremediation for a neat, clean, and evergreen globe. The present study has explored the eco-friendly degradation of complex Reactive Green 12 azo dye to its non-toxic metabolites for safe disposal in an open environment. The bacterial degradation was performed with the variable concentrations (50, 100, 200, 400, and 500 mg/L) of Reactive Green 12 dye. The degradation and toxicity of the dye were validated by high-performance liquid chromatography, Fourier infrared spectroscopy analysis, and phytotoxicity and genotoxicity assay, respectively. The highest 97.8% decolorization was achieved within 12 h. Alternations in the peaks and retentions, thus, along with modifications in the functional groups and chemical bonds, confirmed the degradation of Reactive Green 12. The disappearance of a major peak at 1450 cm-1 corresponding to the -N=N- azo link validated the breaking of azo bonds and degradation of the parent dye. The 100% germination of Triticum aestivum seed and healthy growth of plants verified the lost toxicity of degraded dye. Moreover, the chromosomal aberration of Allium cepa root cell treatment also validated the removal of toxicity through bacterial degradation. Thereafter, for efficient degradation of textile dye, the bacterium is recommended for adaptation to the sustainable degradation of dye and wastewater for further application of degraded metabolites in crop irrigation for sustainable agriculture.


Asunto(s)
Biodegradación Ambiental , Colorantes , Cebollas , Industria Textil , Triticum , Colorantes/metabolismo , Colorantes/química , Colorantes/toxicidad , Triticum/microbiología , Cebollas/efectos de los fármacos , Compuestos Azo/metabolismo , Compuestos Azo/toxicidad , Textiles , Bacterias/metabolismo , Bacterias/efectos de los fármacos , Bacterias/genética , Pruebas de Mutagenicidad
7.
Environ Sci Technol ; 58(20): 8654-8664, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38709862

RESUMEN

Potable reuse water is increasingly part of the water supply portfolio for municipalities facing water shortages, and toxicity assays can be useful for evaluating potable reuse water quality. We examined the Chinese hamster ovary cell acute direct genotoxicity of potable reuse waters contributed by disinfection byproducts (DBPs) and anthropogenic contaminants and used the local conventional drinking waters as benchmarks for evaluating potable reuse water quality. Our results showed that treatment trains based on reverse osmosis (RO) were more effective than RO-free treatment trains for reducing the genotoxicity of influent wastewaters. RO-treated reuse waters were less genotoxic than the local tap water derived from surface water, whereas reuse waters not treated by RO were similarly genotoxic as the local drinking waters when frequent replacement of granular activated carbon limited contaminant breakthrough. The genotoxicity contributed by nonvolatile, uncharacterized DBPs and anthropogenic contaminants accounted for ≥73% of the total genotoxicity. The (semi)volatile DBPs of current research interest contributed 2-27% toward the total genotoxicity, with unregulated DBPs being more important genotoxicity drivers than regulated DBPs. Our results underscore the need to look beyond known, (semi)volatile DBPs and the importance of determining whole water toxicity when assessing the quality of disinfected waters.


Asunto(s)
Cricetulus , Agua Potable , Contaminantes Químicos del Agua , Purificación del Agua , Animales , Células CHO , Contaminantes Químicos del Agua/toxicidad , Desinfección , Cricetinae , Pruebas de Mutagenicidad , Calidad del Agua , Abastecimiento de Agua
8.
Xenobiotica ; 54(6): 266-278, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38819995

RESUMEN

The use of topical photoprotection is necessary to reduce adverse effects caused by excessive exposure to ultraviolet radiation. Despite the high standards set for UV filters, many of them may contribute to the occurrence of adverse effects. The newly synthesised compound K-116, the (E)-cinnamoyl xanthone derivative, could be an alternative. We conducted extended in vitro safety evaluation of compound K-116. The research included assessment of irritation potential on skin tissue, evaluation of penetration through the epidermis, and assessment of phototoxicity, and mutagenicity. Additionally, the eco-safety of compound K-116 was evaluated, including an examination of its degradation pathway in the Cunninghamella echinulata model, as well as in silico simulation of the toxicity of both the parent compound and its degradation products. The research showed that compound K-116 tested in future application conditions is deprived of skin irritant potential additionally it does not penetrate through the epidermis. Results showed that K-116 concentrate is not phototoxic and not mutagenic. The eco-safety studies showed that it undergoes biodegradation in 27% in Cunninghamella echinulata model. The parent compound and formed metabolite are less toxic than reference UV filters (octinoxate and octocrylene).


Asunto(s)
Acrilatos , Protectores Solares , Rayos Ultravioleta , Protectores Solares/toxicidad , Piel/efectos de los fármacos , Piel/metabolismo , Humanos , Pruebas de Mutagenicidad , Animales
9.
Arch Toxicol ; 98(4): 1225-1236, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38427119

RESUMEN

So far, the majority of in vitro toxicological experiments are conducted after an acute 24 h treatment that does not represent a realistic human chemical exposure. Recently, new in vitro approaches have been proposed to study the chemical toxicological effect over several days in order to be more predictive of a representative exposure scenario. In this study, we investigated the genotoxic potential of chemicals (direct or bioactived clastogen, aneugen and apoptotic inducer) with the γH2AX and pH3 biomarkers, in the human liver-derived HepaRP cell line. We used different treatment durations, with or without a three-day recovery stage (release period), before genotoxicity measurement. Data were analysed with the Benchmark Dose approach. We observed that the detection of clastogenic compounds (notably for DNA damaging agents) was more sensitive after three days of repeated treatment compared to one or three treatments over 24 h. In contrast, aneugenic chemicals were detected as genotoxic in a similar manner whether after a 24 h exposure or a three-day repeated treatment. Globally, the release period decreases the genotoxicity measurement substantially. For DNA damaging agents, after high concentration treatments, γH2AX induction was always observed after a three-day release period. In contrast, for DNA topoisomerase inhibitors, no effect could be observed after the release period. In conclusion, in the HepaRP cell line, there are some important differences between a one-day acute and a three-day repeated treatment protocol, indicating that different cell treatment procedures may differentiate chemical genotoxic mechanisms of action more efficiently.


Asunto(s)
Histonas , Mutágenos , Humanos , Histonas/metabolismo , Pruebas de Mutagenicidad/métodos , Mutágenos/toxicidad , Aneugénicos/toxicidad , Daño del ADN , ADN
10.
Arch Toxicol ; 98(10): 3439-3451, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39172143

RESUMEN

Natural non-psychoactive cannabinoids such as cannabigerol (CBG), cannabidiol (CBD), cannabichromene (CBC), cannabidivarin (CBDV), and cannabinol (CBN) are increasingly consumed as constituents of dietary products because of the health benefits claims. Cannabinoids may reduce certain types of pain, nausea, and anxiety. Anti-inflammatory and even anti-carcinogenic properties have been discussed. However, there are insufficient data available regarding their potential (geno-)toxic effects. Therefore, we tested CBG, CBD, CBC, CBDV, and CBN for their genotoxic potential and effects on mitosis and cell cycle in human lymphoblastoid TK6 cells. The selected cannabinoids (except CBDV) induced increased micronuclei formation, which was reduced with the addition of a metabolic activation system (S9 mix). CBDV induced micronuclei only after metabolic activation. Mitotic disturbances were observed with all tested cannabinoids, while G1 phase accumulation of cells was observed for CBG, CBD and CBDV. The genotoxic effects occurred at about 1000-fold higher concentrations than are reported as blood levels from human consumption. However, the results clearly indicate a need for further research into the genotoxic effects of cannabinoids. The mechanism of the mitotic disturbance, the shape of the dose-response curves and the possible effects of mixtures of cannabinoids are aspects which need clarification.


Asunto(s)
Cannabinoides , Linfocitos , Pruebas de Micronúcleos , Mitosis , Mutágenos , Humanos , Cannabinoides/toxicidad , Mitosis/efectos de los fármacos , Linfocitos/efectos de los fármacos , Línea Celular , Mutágenos/toxicidad , Ciclo Celular/efectos de los fármacos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Relación Dosis-Respuesta a Droga , Daño del ADN/efectos de los fármacos , Pruebas de Mutagenicidad , Cannabidiol/toxicidad
11.
Arch Toxicol ; 98(12): 4159-4172, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39259282

RESUMEN

In recent years, nitrosamine impurities in pharmaceuticals have been subject to intense regulatory scrutiny, with nitrosamine drug substance-related impurities (NDSRIs) treated as cohort of concern impurities, regardless of predicted mutagenic potential. Here, we describe a case study of the NDSRI N-nitroso-hydrochlorothiazide (NO-HCTZ), which was positive in the bacterial reverse mutation (Ames) test but is unstable under the test conditions, generating formaldehyde among other products. The mutagenic profile of NO-HCTZ was inconsistent with that expected of a mutagenic nitrosamine, exhibiting mutagenicity in the absence of metabolic activation, and instead aligned well with that of formaldehyde. To assess further, a modified Ames system including glutathione (3.3 mg/plate) to remove formaldehyde was developed. Strains used were S. typhimurium TA98, TA100, TA1535, and TA1537, and E. coli WP2 uvrA/pKM101. In this system, formaldehyde levels were considerably lower, with a concomitant increase in levels of S-(hydroxymethyl)glutathione (the adduct formed between glutathione and formaldehyde). Upon retesting NO-HCTZ in the modified system (1.6-5000 µg/plate), a clear decrease in the mutagenic response was observed in the strains in which NO-HCTZ was mutagenic in the original system (TA98, TA100, and WP2 uvrA/pKM101), indicating that formaldehyde drives the response, not NO-HCTZ. In strain TA1535, an increase in revertant colonies was observed in the modified system, likely due to a thiatriazine degradation product formed from NO-HCTZ under Ames test conditions. Overall, these data support a non-mutagenic designation for NO-HCTZ and demonstrate the value of further investigation when a positive Ames result does not align with the expected profile.


Asunto(s)
Contaminación de Medicamentos , Escherichia coli , Hidroclorotiazida , Pruebas de Mutagenicidad , Mutágenos , Salmonella typhimurium , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Hidroclorotiazida/química , Mutágenos/toxicidad , Formaldehído/toxicidad , Nitrosaminas/toxicidad , Glutatión/metabolismo
12.
Arch Toxicol ; 98(6): 1919-1935, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38584193

RESUMEN

Human liver-derived metabolically competent HepaRG cells have been successfully employed in both two-dimensional (2D) and 3D spheroid formats for performing the comet assay and micronucleus (MN) assay. In the present study, we have investigated expanding the genotoxicity endpoints evaluated in HepaRG cells by detecting mutagenesis using two error-corrected next generation sequencing (ecNGS) technologies, Duplex Sequencing (DS) and High-Fidelity (HiFi) Sequencing. Both HepaRG 2D cells and 3D spheroids were exposed for 72 h to N-nitrosodimethylamine (NDMA), followed by an additional incubation for the fixation of induced mutations. NDMA-induced DNA damage, chromosomal damage, and mutagenesis were determined using the comet assay, MN assay, and ecNGS, respectively. The 72-h treatment with NDMA resulted in concentration-dependent increases in cytotoxicity, DNA damage, MN formation, and mutation frequency in both 2D and 3D cultures, with greater responses observed in the 3D spheroids compared to 2D cells. The mutational spectrum analysis showed that NDMA induced predominantly A:T → G:C transitions, along with a lower frequency of G:C → A:T transitions, and exhibited a different trinucleotide signature relative to the negative control. These results demonstrate that the HepaRG 2D cells and 3D spheroid models can be used for mutagenesis assessment using both DS and HiFi Sequencing, with the caveat that severe cytotoxic concentrations should be avoided when conducting DS. With further validation, the HepaRG 2D/3D system may become a powerful human-based metabolically competent platform for genotoxicity testing.


Asunto(s)
Ensayo Cometa , Daño del ADN , Dimetilnitrosamina , Secuenciación de Nucleótidos de Alto Rendimiento , Pruebas de Micronúcleos , Mutágenos , Humanos , Dimetilnitrosamina/toxicidad , Ensayo Cometa/métodos , Pruebas de Micronúcleos/métodos , Mutágenos/toxicidad , Daño del ADN/efectos de los fármacos , Esferoides Celulares/efectos de los fármacos , Pruebas de Mutagenicidad/métodos , Técnicas de Cultivo de Célula , Línea Celular , Hepatocitos/efectos de los fármacos , Mutagénesis/efectos de los fármacos , Mutación , Relación Dosis-Respuesta a Droga
13.
J Toxicol Environ Health A ; 87(5): 185-198, 2024 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-38073488

RESUMEN

Tellimagrandin-I (TL) and camptothin A (CA) are ellagitannins widely found in diverse plant species. Numerous studies demonstrated their significant biological activities, which include antitumor, antioxidant, and hepatoprotective properties. Despite this protective profile, the effects of TL and CA on DNA have not been comprehensively investigated. Thus, the aim of this study was to determine the mutagenic and antimutagenic effects attributed to TL and CA exposure on Salmonella enterica serovar Typhimurium strains using the Ames test. In addition, the cytotoxic and genotoxic effects were examined on human lymphocytes, employing both trypan blue exclusion and CometChip assay. The antigenotoxic effect was determined following TL and CA exposure in the presence of co-treatment with doxorubicin (DXR). Our results from the Ames test indicated that TL or CA did not display marked mutagenic activity. However, TL or CA demonstrated an ability to protect DNA against the damaging effects of the mutagens 4-nitroquinoline-1-oxide and sodium azide, thereby exhibiting antimutagenic properties. In relation to human lymphocytes, TL or CA did not induce significant cytotoxic or genotoxic actions on these cells. Further, these ellagitannins exhibited an ability to protect DNA from damage induced by DOX during co-treatment, indicating their potential beneficial usefulness as antigenotoxic agents. In conclusion, the protective effects of TL or CA against mutagens, coupled with their absence of genotoxic and cytotoxic effects on human lymphocytes, emphasize their potential therapeutic value in chemopreventive strategies.


Asunto(s)
Antimutagênicos , Salmonella enterica , Humanos , Salmonella typhimurium/genética , Salmonella enterica/genética , Taninos Hidrolizables/farmacología , Serogrupo , Pruebas de Mutagenicidad , Mutágenos/toxicidad , Antimutagênicos/farmacología , Extractos Vegetales/farmacología , Carcinógenos/farmacología , ADN/farmacología , Linfocitos
14.
J Toxicol Environ Health A ; 87(16): 662-673, 2024 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-38808737

RESUMEN

Pseudobombax marginatum, popularly known as "embiratanha," is widely used by traditional communities as anti-inflammatory and analgesic agent. This study aimed to determine the phytochemical profile as well as cytotoxicity, acute oral toxicity, genotoxicity, and mutagenicity attributed to exposure to aqueous (AqEx) and ethanolic (EtEx) extracts of embiratanha bark. Phytochemical screening was conducted using thin-layer chromatography (TLC). Cell viability was analyzed using MTT assay with human mammary gland adenocarcinoma (MDA-MB-231) and macrophage (J774A.1) cell lines, exposed to concentrations of 12.5, 25, 50, or 100 µg/ml of either extract. For acute oral toxicity, comet assay and micronucleus (MN) tests, a single dose of 2,000 mg/kg of either extract was administered orally to Wistar rats. TLC analysis identified classes of metabolites in the extracts, including cinnamic acid derivatives, flavonoids, hydrolyzable tannins, condensed tannins, coumarins, and terpenes/steroids. In the cytotoxicity assay, the varying concentrations of extracts derived from embiratanha induced no significant alterations in the viability of MDA-MB-231 cells. The lowest concentration of EtEx significantly increased macrophage J774A.1 viability. However, the higher concentrations of AqEx markedly lowered macrophage J774A.1 viability. Animals exhibited no toxicity in the parameters analyzed in acute oral toxicity, comet assay, and MN tests. Further, EtEx promoted a significant reduction in DNA damage index and DNA damage frequency utilizing the comet assay, while the group treated with AqEx exhibited no marked differences. Thus, data demonstrated that AqEx or EtEx of embiratanha may be considered safe at a dose of 2,000 mg/kg orgally under our experimental conditions tested.


Asunto(s)
Extractos Vegetales , Ratas Wistar , Extractos Vegetales/toxicidad , Extractos Vegetales/química , Animales , Humanos , Ratas , Línea Celular Tumoral , Masculino , Ensayo Cometa , Pruebas de Micronúcleos , Femenino , Supervivencia Celular/efectos de los fármacos , Fitoquímicos/toxicidad , Fitoquímicos/análisis , Ratones , Corteza de la Planta/química , Mutágenos/toxicidad , Pruebas de Mutagenicidad , Etanol/química
15.
J Toxicol Environ Health A ; 87(14): 592-603, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-38712866

RESUMEN

Punica granatum, popularly known as pomegranate, is a fruit tree with wide worldwide distribution, containing numerous phytochemicals of great medicinal value. The aim of the present study was to determine the phytochemical profile and antioxidant potential of a protein fraction (PF) derived from P. granatum sarcotesta which is rich in lectin. In addition, the acute oral toxicity, genotoxicity and antigenotoxicity of this protein fraction (PF) from P. granatum sarcotesta was measured. The phytochemical profile of PF was determined using HPLC. The in vitro antioxidant effect was assessed using the methods of total antioxidant capacity (TAC) and DPPH and ABTS+ radical scavenging. Acute oral toxicity was determined in female Swiss mice administered a single dose of 2000 mg/kg. This PF was examined for genotoxicity and antigenotoxicity at doses of 500, 1000 and 2000 mg/kg, utilizing mouse peripheral blood cells. Phytochemical characterization detected a high content of ellagic acid and antioxidant capacity similar to that of ascorbic acid (positive control). PF was not toxic (LD50 >2000 mg/kg) and did not exert a genotoxic effect in mice. PF protected the DNA of peripheral blood cells against damage induced by cyclophosphamide. In conclusion, this PF fraction exhibited significant antioxidant activity without initiating toxic or genotoxic responses in mice.


Asunto(s)
Antioxidantes , Extractos Vegetales , Granada (Fruta) , Animales , Ratones , Antioxidantes/farmacología , Femenino , Extractos Vegetales/toxicidad , Extractos Vegetales/química , Extractos Vegetales/farmacología , Granada (Fruta)/química , Lectinas/toxicidad , Pruebas de Mutagenicidad , Daño del ADN/efectos de los fármacos , Pruebas de Toxicidad Aguda
16.
Regul Toxicol Pharmacol ; 152: 105672, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38968965

RESUMEN

Nitrosamine drug substance related impurities or NDSRIs can be formed if an active pharmaceutical ingredient (API) has an intrinsic secondary amine that can undergo nitrosation. This is a concern as 1) nitrosamines are potentially highly potent carcinogens, 2) secondary amines in API are common, and 3) NDSRIs that might form from such secondary amines will be of unknown carcinogenic potency. Approaches for evaluating NDSRIs include read across, quantum mechanical modeling of reactivity, in vitro mutation data, and transgenic in vivo mutation data. These approaches were used here to assess NDSRIs that could potentially form from the drugs fluoxetine, duloxetine and atomoxetine. Based on a read across informed by modeling of physicochemical properties and mechanistic activation from quantum mechanical modeling, NDSRIs of fluoxetine, duloxetine, and atomoxetine were 10-100-fold less potent compared with highly potent nitrosamines such as NDMA or NDEA. While the NDSRIs were all confirmed to be mutagenic in vitro (Ames assay) and in vivo (TGR) studies, the latter data indicated that the potency of the mutation response was ≥4400 ng/day for all compounds-an order of magnitude higher than published regulatory limits for these NDSRIs. The approaches described herein can be used qualitatively to better categorize NDSRIs with respect to potency and inform whether they are in the ICH M7 (R2) designated Cohort of Concern.


Asunto(s)
Clorhidrato de Atomoxetina , Clorhidrato de Duloxetina , Fluoxetina , Pruebas de Mutagenicidad , Clorhidrato de Duloxetina/toxicidad , Clorhidrato de Atomoxetina/toxicidad , Fluoxetina/toxicidad , Animales , Nitrosaminas/toxicidad , Mutágenos/toxicidad , Humanos , Ratones
17.
Regul Toxicol Pharmacol ; 151: 105670, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38936798

RESUMEN

Given the widespread applications in industrial and agricultural production, the health effects of rare earth elements (REEs) have garnered public attention, and the genotoxicity of REEs remains unclear. In this study, we evaluated the genetic effects of lanthanum nitrate, a typical representative of REEs, with guideline-compliant in vivo and in vitro methods. Genotoxicity assays, including the Ames test, comet assay, mice bone marrow erythrocyte micronucleus test, spermatogonial chromosomal aberration test, and sperm malformation assay were conducted to assess mutagenicity, chromosomal damage, DNA damage, and sperm malformation. In the Ames test, no statistically significant increase in bacterial reverse mutation frequencies was found as compared with the negative control. Mice exposed to lanthanum nitrate did not exhibit a statistically significant increase in bone marrow erythrocyte micronucleus frequencies, spermatogonial chromosomal aberration frequencies, or sperm malformation frequencies compared to the negative control (P > 0.05). Additionally, after a 24-h treatment with lanthanum nitrate at concentrations of 1.25, 5, and 20 µg/ml, no cytotoxicity was observed in CHL cells. Furthermore, the comet assay results indicate no significant DNA damage was observed even after exposure to high doses of lanthanum nitrate (20 µg/ml). In conclusion, our findings suggest that lanthanum nitrate does not exhibit genotoxicity.


Asunto(s)
Aberraciones Cromosómicas , Ensayo Cometa , Daño del ADN , Lantano , Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Espermatozoides , Lantano/toxicidad , Animales , Masculino , Ratones , Daño del ADN/efectos de los fármacos , Pruebas de Mutagenicidad/métodos , Aberraciones Cromosómicas/inducido químicamente , Aberraciones Cromosómicas/efectos de los fármacos , Ensayo Cometa/métodos , Pruebas de Micronúcleos/métodos , Espermatozoides/efectos de los fármacos , Mutágenos/toxicidad , Relación Dosis-Respuesta a Droga , Ratones Endogámicos ICR , Línea Celular
18.
Regul Toxicol Pharmacol ; 153: 105709, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39343352

RESUMEN

Accurately determining the mutagenicity of small-molecule N-nitrosamine drug impurities and nitrosamine drug substance-related impurities (NDSRIs) is critical to identifying mutagenic and cancer hazards. In the current study we have evaluated several approaches for enhancing assay sensitivity for evaluating the mutagenicity of N-nitrosamines in the bacterial reverse mutagenicity (Ames) test. Preincubation assays were conducted using five activation conditions: no exogenous metabolic activation and metabolic activation mixes employing both 10% and 30% liver S9 from hamsters and rats pretreated with inducers of enzymatic activity. In addition, preincubations were conducted for both 60 min and 30 min. These test variables were evaluated by testing 12 small-molecule N-nitrosamines and 17 NDSRIs for mutagenicity in Salmonella typhimurium tester strains TA98, TA100, TA1535, and TA1537, and Escherichia coli strain WP2 uvrA (pKM101). Eighteen of the 29 N-nitrosamine test substances tested positive under one or more of the testing conditions and all 18 positives could be detected by using tester strains TA1535 and WP2 uvrA (pKM101), preincubations of 30 min, and S9 mixes containing 30% hamster liver S9. In general, the conditions under which NDSRIs were mutagenic were similar to those found for small-molecule N-nitrosamines.


Asunto(s)
Pruebas de Mutagenicidad , Mutágenos , Nitrosaminas , Salmonella typhimurium , Pruebas de Mutagenicidad/métodos , Animales , Nitrosaminas/toxicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Ratas , Mutágenos/toxicidad , Cricetinae , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Masculino , Contaminación de Medicamentos , Hígado/efectos de los fármacos , Hígado/metabolismo , Activación Metabólica
19.
Regul Toxicol Pharmacol ; 150: 105641, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38723937

RESUMEN

In dietary risk assessment of plant protection products, residues of active ingredients and their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity, in terms of metabolism, a metabolic similarity profiling scheme has been developed from an analysis of 69 α-chloroacetamide herbicides for which either Ames, chromosomal aberration or micronucleus test results are publicly available. A set of structural space alerts were defined, each linked to a key metabolic transformation present in the α-chloroacetamide metabolic space. The structural space alerts were combined with covalent chemistry profiling to develop categories suitable for chemical prioritisation via read-across. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for metabolism data individual groups of plant protection products as the basis for the development of the structural space alerts.


Asunto(s)
Acetamidas , Herbicidas , Pruebas de Mutagenicidad , Acetamidas/toxicidad , Acetamidas/química , Medición de Riesgo , Herbicidas/toxicidad , Herbicidas/química , Residuos de Plaguicidas/toxicidad , Humanos , Mutágenos/toxicidad , Mutágenos/química , Animales
20.
Regul Toxicol Pharmacol ; 152: 105681, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39067806

RESUMEN

The finding of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in marketed drugs has led to implementation of risk assessment processes intended to limit exposures to the entire class of N-nitrosamines. A critical component of the risk assessment process is establishing exposure limits that are protective of human health. One approach to establishing exposure limits for novel N-nitrosamines is to conduct an in vivo transgenic rodent (TGR) mutation study. Existing regulatory guidance on N-nitrosamines provides decision making criteria based on interpreting in vivo TGR mutation studies as an overall positive or negative. However, point of departure metrics, such as benchmark dose (BMD), can be used to define potency and provide an opportunity to establish relevant exposure limits. This can be achieved through relative potency comparison of novel N-nitrosamines with model N-nitrosamines possessing robust in vivo mutagenicity and carcinogenicity data. The current work adds to the dataset of model N-nitrosamines by providing in vivo TGR mutation data for N-nitrosopiperidine (NPIP). In vivo TGR mutation data was also generated for a novel N-nitrosamine impurity identified in sitagliptin-containing products, 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine (NTTP). Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day.


Asunto(s)
Contaminación de Medicamentos , Mutación , Nitrosaminas , Animales , Medición de Riesgo , Nitrosaminas/toxicidad , Mutación/efectos de los fármacos , Pruebas de Mutagenicidad/métodos , Mutágenos/toxicidad , Ratones , Relación Dosis-Respuesta a Droga , Dimetilnitrosamina/toxicidad , Animales Modificados Genéticamente , Dietilnitrosamina/toxicidad , Humanos , Carcinógenos/toxicidad , Ratas , Masculino
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA