RESUMO
The potential connection between exposure to glyphosate and glyphosate-based herbicides (GBHs) and breast cancer risk is a topic of research that is rapidly gaining the public's attention due to the conflicting reports surrounding glyphosate's potential carcinogenicity. In this review, we synthesize the current published biomedical literature works that have explored associations of glyphosate, its metabolite, aminomethylphosphonic acid (AMPA), and GBHs with breast cancer risk in humans and human cell-based models. Using PubMed as our search engine, we identified a total of 14 articles that were included in this review. In the four human studies, urinary glyphosate and/or AMPA were associated with breast cancer risk, endocrine disruption, oxidative stress biomarkers, and changes in DNA methylation patterns. Among most of the 10 human cell-based studies, glyphosate exhibited endocrine disruption, induced altered gene expression, increased DNA damage, and altered cell viability, while GBHs were more cytotoxic than glyphosate alone. In summary, numerous studies have shown glyphosate, AMPA, and GBHs to have potential carcinogenic, cytotoxic, or endocrine-disruptive properties. However, more human studies need to be conducted in order for more definitive and supported conclusions to be made on their potential effects on breast cancer risk.
Assuntos
Neoplasias da Mama , Glicina , Glifosato , Herbicidas , Humanos , Glicina/análogos & derivados , Glicina/toxicidade , Herbicidas/toxicidade , Neoplasias da Mama/induzido quimicamente , Feminino , Organofosfonatos/toxicidadeRESUMO
Glyphosate is the most widely used systemic herbicide. There is ample scientific literature on the effects of this compound and its metabolite aminomethylphosphonic acid (AMPA), whereas their possible combined genotoxic action has not yet been studied. With the present study, we aimed to determine the level of genomic damage caused by glyphosate and AMPA in cultured human lymphocytes and to investigate the possible genotoxic action when both compounds were present at the same concentrations in the cultures. We used a micronuclei assay to test the genotoxicity of glyphosate and AMPA at six concentrations (0.0125, 0.025, 0.050, 0.100, 0.250, 0.500 µg/mL), which are more realistic than the highest concentrations used in previous published studies. Our data showed an increase in micronuclei frequency after treatment with both glyphosate and AMPA starting from 0.050 µg/mL up to 0.500 µg/mL. Similarly, a genomic damage was observed also in the cultures treated with the same concentrations of both compounds, except for exposure to 0.0065 and 0.0125 µg/mL. No synergistic action was observed. Finally, a significant increase in apoptotic cells was observed in cultures treated with the highest concentration of tested xenobiotics, while a significant increase in necrotic cells was observed also at the concentration of 0.250 µg/mL of both glyphosate and AMPA alone and in combination (0.125 + 0.125 µg/mL). Results of our study indicate that both glyphosate and its metabolite AMPA are able to cause genomic damage in human lymphocyte cultures, both alone and when present in equal concentrations.
Assuntos
Dano ao DNA , Glicina , Glifosato , Herbicidas , Linfócitos , Testes para Micronúcleos , Organofosfonatos , Glicina/análogos & derivados , Glicina/toxicidade , Humanos , Herbicidas/toxicidade , Linfócitos/efeitos dos fármacos , Organofosfonatos/toxicidade , Mutagênicos/toxicidade , Adulto , MasculinoRESUMO
Aminomethylphosphonic acid (AMPA) is the main metabolite in the degradation of glyphosate, a broad-spectrum herbicide, and it is more toxic and persistent in the environment than the glyphosate itself. Owing to their extensive use, both chemicals pose a serious risk to aquatic ecosystems. Here, we explored the genotoxicological and physiological effects of glyphosate, AMPA, and the mixed solution in the proportion 1:1 in Lymnaea stagnalis, a freshwater gastropod snail. To do this, adult individuals were exposed to increasing nominal concentrations (0.0125, 0.025, 0.050, 0.100, 0.250, 0.500 µg/mL) in all three treatments once a week for four weeks. The genotoxicological effects were estimated as genomic damage, as defined by the number of micronuclei and nuclear buds observed in hemocytes, while the physiological effects were estimated as the effects on somatic growth and egg production. Exposure to glyphosate, AMPA, and the mixed solution caused genomic damage, as measured in increased frequency of micronuclei and nuclear buds and in adverse effects on somatic growth and egg production. Our findings suggest the need for more research into the harmful and synergistic effects of glyphosate and AMPA and of pesticides and their metabolites in general.
Assuntos
Glicina , Glifosato , Herbicidas , Lymnaea , Organofosfonatos , Poluentes Químicos da Água , Animais , Glicina/análogos & derivados , Glicina/toxicidade , Lymnaea/efeitos dos fármacos , Lymnaea/genética , Poluentes Químicos da Água/toxicidade , Organofosfonatos/toxicidade , Herbicidas/toxicidade , Testes para Micronúcleos , Dano ao DNA/efeitos dos fármacos , Hemócitos/efeitos dos fármacos , Tetrazóis/toxicidadeRESUMO
Environmental exposure to endocrine disruptors, such as pesticides, could contribute to a decline of human fertility. Glyphosate (GLY) is the main component of Glyphosate Based Herbicides (GBHs), which are the most commonly herbicides used in the world. Various animal model studies demonstrated its reprotoxicity. In Europe, GLY authorization in agriculture has been extended until 2034. Meanwhile the toxicity of GLY in humans is still in debate. The aims of our study were firstly to analyse the concentration of GLY and its main metabolite, amino-methyl-phosphonic acid (AMPA) by LC/MS-MS in the seminal and blood plasma in an infertile French men population (n=128). We secondly determined Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) using commercial colorimetric kits and some oxidative stress biomarkers including malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) by ELISA assays. We next analysed potential correlations between GLY and oxidative stress biomarkers concentration and sperm parameters (sperm concentration, progressive speed, anormal forms). Here, we detected for the first time GLY in the human seminal plasma in significant proportions and we showed that its concentration was four times higher than those observed in blood plasma. At the opposite, AMPA was undetectable. We also observed a strong positive correlation between plasma blood GLY concentrations and plasma seminal GLY and 8-OHdG concentrations, the latter reflecting DNA impact. In addition, TOS, Oxidative Stress Index (OSI) (TOS/TAS), MDA blood and seminal plasma concentrations were significantly higher in men with glyphosate in blood and seminal plasma, respectively. Taken together, our results suggest a negative impact of GLY on the human reproductive health and possibly on his progeny. A precaution principle should be applied at the time of the actual discussion of GLY and GBHs formulants uses in Europe by the authorities.
Assuntos
Glicina , Glifosato , Herbicidas , Infertilidade Masculina , Estresse Oxidativo , Espermatozoides , Humanos , Masculino , Glicina/análogos & derivados , Glicina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , França , Adulto , Herbicidas/toxicidade , Espermatozoides/efeitos dos fármacos , Infertilidade Masculina/induzido quimicamente , Sêmen/efeitos dos fármacos , Biomarcadores/sangue , Malondialdeído/metabolismo , Organofosfonatos/toxicidade , Pessoa de Meia-IdadeRESUMO
Organic anion transporters 1 (OAT1) and OAT3 are responsible for transporting adefovir (ADV) into renal tubular epithelial cells. Our previous research found that ADV accumulated in the renal interstitium and caused renal interstitial fibrosis when Oat1/3 were inhibited by OATs inhibitor probenecid for long-term. Mast cells (MCs) in the interstitial space are considered to be key drivers of renal fibrosis. The current work investigated the effect of ADV on MCs in vitro and during the development of interstitial fibrosis in rats. Results indicate that ADV triggers chymase release from cultured RBL-2H3 mast cells in a time-and concentration-dependent manner. Angiotensin II (Ang II) in renal interstitium is generated mainly by chymase, renin and other products released from MCs, and has a direct effect on fibrosis through the angiotensin receptor. The concentrations of Ang II and fibrosis was significantly increased after administration of ADV alone or with probenecid for 4 weeks. The MCs membrane stabilizer sodium cromoglycate (SCG) and the angiotensin receptor antagonist Valsartan (VAL) could ameliorate ADV-induced nephrotoxicity. Additionally, SCG or VAL could reduce the accumulation of ADV in the renal interstitium by upregulating the expression of Oat1/3 and multidrug resistance-associated protein 4. Therefore, ADV accumulation in the renal interstitium could promote the degranulation of interstitial MCs and drive the development of renal fibrosis. SCG or VAL could ameliorate ADV-associated fibrosis by decreasing degranulation of MCs and accelerating renal clearance of ADV.
Assuntos
Adenina/análogos & derivados , Adenina/toxicidade , Degranulação Celular/efeitos dos fármacos , Fibrose/induzido quimicamente , Nefropatias/induzido quimicamente , Mastócitos/efeitos dos fármacos , Organofosfonatos/toxicidade , Adenina/sangue , Animais , Modelos Animais de Doenças , Fibrose/fisiopatologia , Humanos , Nefropatias/fisiopatologia , Túbulos Renais/efeitos dos fármacos , Masculino , Organofosfonatos/sangue , RatosRESUMO
BACKGROUND: Glyphosate (GLY) is the most heavily used herbicide in the world. Despite nearly ubiquitous exposure, few studies have examined prenatal GLY exposure and potentially adverse pregnancy outcomes. Preterm birth (PTB) is a risk factor for neonatal mortality and adverse health effects in childhood. OBJECTIVES: We examined prenatal exposure to GLY and a highly persistent environmental degradate of GLY, aminomethylphosphonic acid (AMPA), and odds of PTB in a nested case-control study within the ongoing Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort in northern Puerto Rico. METHODS: GLY and AMPA in urine samples collected at 18±2 (Visit 1) and 26±2 (Visit 3) wk gestation (53 cases/194 randomly selected controls) were measured using gas chromatography tandem mass spectrometry. Multivariable logistic regression was used to estimate associations with PTB (delivery <37wk completed gestation). RESULTS: Detection rates in controls were 77.4% and 77.5% for GLY and 52.8% and 47.7% for AMPA, and geometric means (geometric standard deviations) were 0.44 (2.50) and 0.41 (2.56) µg/L for GLY and 0.25 (3.06) and 0.20 (2.87) µg/L for AMPA, for Visits 1 and 3, respectively. PTB was significantly associated with specific gravity-corrected urinary GLY and AMPA at Visit 3, whereas associations with levels at Visit 1 and the Visits 1-3 average were largely null or inconsistent. Adjusted odds ratios (ORs) for an interquartile range increase in exposure at Visit 3 were 1.35 (95% CI: 0.99, 1.83) and 1.67 (95% CI: 1.26, 2.20) for GLY and AMPA, respectively. ORs for Visit 1 and the visit average were closer to the null. DISCUSSION: Urine GLY and AMPA levels in samples collected near the 26th week of pregnancy were associated with increased odds of PTB in this modestly sized nested case-control study. Given the widespread use of GLY, multiple potential sources of AMPA, and AMPA's persistence in the environment, as well as the potential for long-term adverse health effects in preterm infants, further investigation in other populations is warranted. https://doi.org/10.1289/EHP7295.
Assuntos
Glicina/análogos & derivados , Organofosfonatos , Nascimento Prematuro , Efeitos Tardios da Exposição Pré-Natal , Estudos de Casos e Controles , Feminino , Glicina/toxicidade , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Organofosfonatos/toxicidade , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Porto Rico/epidemiologia , GlifosatoRESUMO
Pantoea ananatis is the primary cause of onion center rot. Genetic data suggest that a phosphonic acid natural product is required for pathogenesis; however, the nature of the molecule is unknown. Here, we show that P. ananatis produces at least three phosphonates, two of which were purified and structurally characterized. The first, designated pantaphos, was shown to be 2-(hydroxy[phosphono]methyl)maleate; the second, a probable biosynthetic precursor, was shown to be 2-(phosphonomethyl)maleate. Purified pantaphos is both necessary and sufficient for the hallmark lesions of onion center rot. Moreover, when tested against mustard seedlings, the phytotoxic activity of pantaphos was comparable to the widely used herbicides glyphosate and phosphinothricin. Pantaphos was also active against a variety of human cell lines but was significantly more toxic to glioblastoma cells. Pantaphos showed little activity when tested against a variety of bacteria and fungi.IMPORTANCEPantoea ananatis is a significant plant pathogen that targets a number of important crops, a problem that is compounded by the absence of effective treatments to prevent its spread. Our identification of pantaphos as the key virulence factor in onion center rot suggests a variety of approaches that could be employed to address this significant plant disease. Moreover, the general phytotoxicity of the molecule suggests that it could be developed into an effective herbicide to counter the alarming rise in herbicide-resistant weeds.
Assuntos
Produtos Biológicos/toxicidade , Cebolas/microbiologia , Organofosfonatos/toxicidade , Pantoea/metabolismo , Doenças das Plantas/microbiologia , Organofosfonatos/química , Organofosfonatos/metabolismo , Organofosfonatos/farmacologia , Doenças das Plantas/etiologiaRESUMO
Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc-binding group (ZBG) variants of this thiol-derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development.
Assuntos
Acetanilidas/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Quelantes/farmacologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Organofosfonatos/farmacologia , Acetanilidas/síntese química , Acetanilidas/toxicidade , Animais , Bacillus cereus/enzimologia , Proteínas de Bactérias/metabolismo , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/toxicidade , Clostridium histolyticum/enzimologia , Colágeno/metabolismo , Colagenases/metabolismo , Células HEK293 , Humanos , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/toxicidade , Organofosfonatos/síntese química , Organofosfonatos/toxicidade , Suínos , Peixe-Zebra , Zinco/químicaRESUMO
Despite intense societal and scientific debates regarding glyphosate toxicity, it remains the most widely used herbicide. The primary metabolite of glyphosate, AMPA (aminomethylphosphonic acid), is the main contaminant detected in surface waters worldwide, both because of the extensive use of glyphosate and because of other widespread sources of AMPA (i.e., industrial detergents). Studies on potential effects of glyphosate using environmentally relevant concentrations of AMPA on non-target wildlife species are lacking. We experimentally tested the effects of AMPA on embryonic development in a common European toad at concentrations spanning the range found in natural water bodies (from 0.07 to 3.57 µg l-1). Our experimental concentrations of AMPA were 100-6000 times lower than official Predicted-No-Effect-Concentrations. We found that these low-level concentrations of AMPA decreased embryonic survival, increased development duration and influenced hatchling morphology. Response patterns were more complex than classical linear concentration-response relationships, as concentration responses were nonmonotonic, with greater effects at low-concentrations of AMPA than at high levels. Based on our results we recommend that investigators focus not only on effects of "parent compounds," but also their metabolites at environmentally relevant concentrations in order to comprehensively assess impacts of anthropogenic contaminants on the environment.
Assuntos
Herbicidas , Organofosfonatos , Anfíbios , Animais , Desenvolvimento Embrionário , Monitoramento Ambiental , Herbicidas/análise , Herbicidas/toxicidade , Isoxazóis , Organofosfonatos/toxicidade , TetrazóisRESUMO
This review provides an overview of the global research leading to the large number of compounds developed as reactivators of acetylcholinesterase inhibited by a variety of organophosphate compounds, most of which are nerve agents but also some insecticides. A number of these organophosphates are highly toxic and effective therapy by reactivators contributes to saving lives. Two major challenges for more effective therapy with reactivators are identification of a broad spectrum reactivator efficacious against a variety of organophosphate structures, and a reactivator that can cross the blood-brain barrier to protect the brain. The most effective of the reactivators developed are the nucleophilic pyridinium oximes, which bear a permanent positive charge from the quaternary nitrogen in the pyridinium ring. The permanent positive charge retards the oximes from crossing the blood-brain barrier and therefore restoration of normal cholinergic function in the brain is unlikely. A number of laboratories have developed nucleophiles, mostly oximes, that are theorized to cross the blood-brain barrier by several strategies. At the present time, no reactivator is optimally broad spectrum across the wide group of organophosphate chemistries. Some oximes, including the substituted phenoxyalkyl pyridinium oximes invented by our laboratories, have the potential to provide neuroprotection in the brain and show evidence of efficacy against both nerve agent and insecticidal chemistries, so these novel oximes have promise for future development. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.
Assuntos
Acetilcolinesterase/farmacologia , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Organofosfonatos/toxicidade , Oximas/farmacologia , Animais , Humanos , CamundongosRESUMO
Aminomethylphosphonic acid (AMPA) is a primary metabolite of glyphosate and amino-polyphosphonate. We have determined the effect of AMPA on selected epigenetic parameters and major cell cycle drivers in human peripheral blood mononuclear cells (PBMCs). The cells were incubated with AMPA at 0.5, 10 and 250⯵M for 24â¯h. The performed analysis included: global DNA methylation by colorimetric measurement of 5-methylcytosine in DNA, methylation in the promoter regions of selected tumor suppressor genes (P16, P21, TP53) and proto-oncogenes (BCL2, CCND1) as well as the expression profile of the indicated genes by Real-Time PCR assays. The obtained results have revealed significant reduction of global DNA methylation level in PBMCs exposed to AMPA. Investigated xenobiotic changed methylation pattern of the P21 and TP53 suppressor gene promoters, but in case of other analyzed genes: P16, BCL2 and CCND1 no statistically significant changes have been noted. Gene profiling have shown that AMPA only changed the expression of CCND1. Summing up, our results have revealed a small potential disturbance in methylation processes and the absence of changes in expression of tested tumor suppressor genes (P16, P21, TP53) and protooncogenes (BCL2) in human PBMCs exposed to AMPA.
Assuntos
Leucócitos Mononucleares/efeitos dos fármacos , Organofosfonatos/toxicidade , Células Cultivadas , Ciclina D1/genética , Metilação de DNA , Epigênese Genética , Genes Supressores de Tumor , Glicina/análogos & derivados , Glicina/metabolismo , Herbicidas/metabolismo , Humanos , Regiões Promotoras Genéticas , GlifosatoRESUMO
A set of phosphonate prodrugs of a butyrophilin ligand was synthesized and evaluated for plasma stability and cellular activity. The mixed aryl acyloxy esters were prepared either via a standard sequence through the phosphonic acid chloride, or through the more recently reported, and more facile, triflate activation. In the best of cases, this class of prodrugs shows cellular potency similar to that of bis-acyloxyalkyl phosphonate prodrugs and plasma stability similar to that of aryl phosphonamidates. For example, {[((3E)-5-hydroxy-4-methylpent-3-en-1-yl) (naphthalen-2-yloxy)phosphoryl]oxy}methyl 2,2-dimethylpropanoate can activate BTN3A1 in K562 cells after just 15â minutes of exposure (at an EC50 value of 31â nm) and is only partially metabolized (60 % remaining) after 20â hours in human plasma. Other related novel analogues showed similar potency/stability profiles. Therefore, mixed aryl acyloxyalkyl phosphonate prodrugs are an exciting new strategy for the delivery of phosphonate-containing drugs.
Assuntos
Butirofilinas/farmacologia , Organofosfonatos/farmacologia , Pró-Fármacos/farmacologia , Butirofilinas/sangue , Butirofilinas/síntese química , Butirofilinas/toxicidade , Estabilidade de Medicamentos , Humanos , Células K562 , Organofosfonatos/sangue , Organofosfonatos/síntese química , Organofosfonatos/toxicidade , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidadeRESUMO
Common characteristics of drug induced nephrotoxicity are renal tubular and interstitial injury. Many studies have only focused on renal tubular injury. However, less is known about the effects of drugs in the renal interstitium on the nephrotoxicity. The aim of this study was to investigate the pharmacokinetics of adefovir (ADV) and the nephrotoxicity in the renal interstitium. Rats were treated with ADV alone or in combination with probenecid for 1, 7, 14, or 28â¯days. The renal interstitial fluid was collected by renal microdialysis. The concentration of ADV was determined by HPLC-MS/MS. Nephrotoxicity was evaluated by biochemical parameters or histological analysis. The results showed that organic anion transporters (OATs) inhibitor probenecid significantly increased the area under concentration-time curves (AUC) and peak concentration (Cmax) of ADV in the renal interstitium, while the clearance (CL) in the renal interstitium was decreased in the ADV plus probenecid group compared to the ADV groups. After long-term treatment, interstitial fibrosis was present in the ADV plus probenecid group, whereas no trace of that could be detected in the ADV groups. Furthermore, a decrease was observed in the expression of OATs/Oats, which was dependent upon the concentrations and time of ADV treatment. In conclusion, it is possible that ADV could be accumulated in the interstitium when Oats were inhibited, which could cause renal interstitial fibrosis. Simply reducing cell uptake in long-term treatment might not be an effective method to protect against chronic nephrotoxicity.
Assuntos
Adenina/análogos & derivados , Nefropatias/induzido quimicamente , Túbulos Renais/patologia , Transportadores de Ânions Orgânicos/metabolismo , Organofosfonatos/farmacocinética , Organofosfonatos/toxicidade , Adenina/farmacocinética , Adenina/toxicidade , Animais , Antivirais/farmacocinética , Antivirais/toxicidade , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
Tuberculosis (TB) is the leading cause of death worldwide due to bacterial infection. The scarcity of effective drugs to treat the disease and the compounded problems due to the development of resistance to the available therapeutics and TB-HIV synergism drive medicinal chemists to search for new anti-Mtb chemotypes. Towards this endeavor, the α-sulfonamidophosphonate moiety has been identified as new anti-Mtb chemotype through the scaffold hopping as the design strategy, development of an effective synthetic methodology using green chemistry tools, and evaluation of anti-TB activity of the synthesized compounds against Mtb (Mycobacterium tuberculosis) H37Rv. Out of the sixteen compounds, five have been found to have MIC values of 1.56⯵g/mL and one 3.125⯵g/mL. The five most active compounds are non-cytotoxic to RAW 264.7 (mouse leukemic monocyte macrophage) cell lines. The compounds are found to possess acceptable values of the various parameters for drug likeness in accordance with the Lipinski rule with the topological surface area (tPSA) of >70 that suggest eligibility of these new molecular entities for further consideration as potential drug candidates.
Assuntos
Antituberculosos/farmacologia , Organofosfonatos/farmacologia , Sulfonamidas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/toxicidade , Desenho de Fármacos , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Organofosfonatos/síntese química , Organofosfonatos/química , Organofosfonatos/toxicidade , Células RAW 264.7 , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidadeRESUMO
Numerous research works have shown that synthesis of pesticides leads to the formation of impurities that may substantially enhance pesticide toxicity. In this study, the effect of manufacturing impurities of pesticide bromfenvinphos (BFVF) such as 1-bromo-2-(2,4-dichlorophenyl)-2-ethoxy ethene (BDCEE) and diethyl [2-(2,4-dichlorophenyl)-2-oxo-ethyl] phosphonate (ß-ketophosphonate) on human erythrocytes, being significantly exposed to xenobiotics has been studied. The cells were treated with the compounds studied in the concentrations ranging from 0.1 µM to 250 µM for 4 h. In order to assess the effect of BDCEE and ß-ketophosphonate on red blood cells hemolytic changes, changes in cell size (FSC parameter) and oxidation of hemoglobin were studied. Moreover, alterations in reactive oxygen species (ROS) formation, reduced glutathione (GSH) level and acetylcholinesterase (AChE) activity were determined. BDCEE induced an increase in ROS level and caused strong oxidation of hemoglobin as well as a slight change in erythrocytes size and hemolysis, while it did not change GSH level and AChE activity. ß-ketophosphonate has not been shown to affect most parameters studied, but it strongly reduced AChE activity. Because changes in the parameters examined were noted at low concentrations of BFVF impurities (5-250 µM), those substances should not negatively affect on red blood cells of humans environmentally exposed to this pesticide.
Assuntos
Acetilcolinesterase/metabolismo , Clorfenvinfos/análogos & derivados , Clorofenóis/toxicidade , Eritrócitos/efeitos dos fármacos , Etilenos/toxicidade , Organofosfonatos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/toxicidade , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Clorfenvinfos/química , Clorfenvinfos/toxicidade , Clorofenóis/química , Contaminação de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/fisiologia , Etil-Éteres/química , Etil-Éteres/toxicidade , Etilenos/química , Glutationa/metabolismo , Humanos , Organofosfonatos/química , Oxirredução , Praguicidas/química , Testes de ToxicidadeRESUMO
Structural and electronic properties of a series of 25 phosphonate derivatives were analyzed applying density functional theory, with the exchange-correlation functional PBEPBE in combination with the 6-311++G** basis set for all atoms. The chemical reactivity of these derivatives has been interpreted using quantum descriptors such as frontier molecular orbitals (HOMO, LUMO), Hirshfeld charges, molecular electrostatic potential, and the dual descriptor [[Formula: see text]]. These descriptors are directly related to experimental median lethal dose ([Formula: see text], expressed as its decimal logarithm [[Formula: see text]([Formula: see text]] through a multiple linear regression equation. The proposed model predicts the toxicity of phosphonates in function of the volume (V), the load of the most electronegative atom of the molecule (q), and the eigenvalue of the molecular orbital HOMO ([Formula: see text]. The obtained values in the internal validation of the model are: [Formula: see text]%, [Formula: see text]%, [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text]%. The toxicity of nine phosphonate derivatives used as test molecules was adequately predicted by the model. The theoretical results indicate that the oxygen atom of the O=P group plays an important role in the interaction mechanism between the phosphonate and the acetylcholinesterase enzyme, inhibiting the removal of the proton of the ser-200 residue by the his-440 residue.
Assuntos
Simulação por Computador , Organofosfonatos/química , Organofosfonatos/toxicidade , Relação Quantitativa Estrutura-Atividade , Elétrons , Dose Letal Mediana , Modelos Moleculares , Conformação MolecularRESUMO
Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The pathophysiology of drug-induced Fanconi syndrome is unclear. Here we report the case of a 36-year-old woman who presented with pain in multiple bones and proteinuria. She had a 7-year history of taking adefovir at 10 mg/day for chronic hepatitis B. Three years previously she had received surgery for a nontraumatic right femur neck fracture, after which she continued to complain of pain in multiple bones, and proteinuria, glycosuria, and phosphaturia were noted. The findings of a light-microscope examination of a renal biopsy sample were normal, but mitochondrial damage of the proximal tubules was evident in electron microscopy. Western blot analysis revealed that the level of serum fibroblast growth factor 23 (FGF23) was lower than in normal controls. After 2 months of treatment, hypophosphatemia and proximal tubular dysfunction were reversed, and serum FGF23 had normalized. This case suggests that direct mitochondrial damage in proximal tubules can cause drug-induced Fanconi syndrome associated with osteomalacia.
Assuntos
Adenina/análogos & derivados , Síndrome de Fanconi/diagnóstico , Organofosfonatos/efeitos adversos , Osteomalacia/diagnóstico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adenina/toxicidade , Adulto , Osso e Ossos/efeitos dos fármacos , Síndrome de Fanconi/etiologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Hepatite B/tratamento farmacológico , Humanos , Hipofosfatemia/etiologia , Hipofosfatemia/patologia , Túbulos Renais Proximais/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Organofosfonatos/uso terapêutico , Organofosfonatos/toxicidade , Osteomalacia/etiologiaRESUMO
This study was performed to evaluate the protective efficacy of metoclopramide (MCP) against the organophosphates paraoxon (POX)- and malathion (MLT)-induced apoptosis in the murine L929 skin fibroblasts. L929 cells were exposed to either POX (10 nm) or 1.0 µm MLT in the absence and presence of increased concentrations of MCP. The protective effect of MCP on these organophosphate-stimulated apoptotic events was evaluated by flow cytometry analysis after staining with annexin-V/propidium iodide, processing and activation of the executioner caspase-3, cleavage of the poly-ADP ribose polymerase, fragmentation of the nucleosomal DNA and disruption of the mitochondrial membrane potential (Δψ). Our results showed that increased doses of MCP alone (≥10 µm) did not induce apoptosis or activation of caspase-3. Pretreatment of the cells with MCP attenuated all the apoptotic events triggered by the organophosphate compounds in a dose-dependent manner reaching ~70-80% protection when they were preincubated at 1 and 5 µm of the drug before the addition of POX and MLT, respectively. Interestingly, MCP did not offer a significant protective effect against the cytotoxicity of tumor necrosis factor-α, cisplatinum, etoposide or paclitaxel, which stimulate apoptosis by various mechanisms, suggesting that the anti-apoptotic effect of the drug is specific to organophosphates. The strong and specific anti-apoptotic activity of subclinical doses of MCP against the cytotoxicity of organophosphate compounds suggests its potential clinical application in treating their poisoning.
Assuntos
Antídotos/farmacologia , Apoptose/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Malation/toxicidade , Metoclopramida/farmacologia , Organofosfonatos/toxicidade , Paraoxon/toxicidade , Pele/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Linhagem Celular , Citoproteção , Relação Dose-Resposta a Droga , Fibroblastos/metabolismo , Fibroblastos/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Poli(ADP-Ribose) Polimerases/metabolismo , Pele/metabolismo , Pele/patologiaRESUMO
BACKGROUND: Apigenin is a flavonoid compound, widely distributed in natural plants. Various studies have suggested that apigenin has inhibitory effects towards several drug transporters, such as the organic anion transporting (OAT) polypeptides, 1B1 and 1B3 (OATP1B1 and OATP1B3). However, the mechanism by which apigenin interacts with OAT1 has not been well studied. METHODS: MDCK cells stably-expressing OAT1 were used to examine the inhibitory effects of apigenin on OAT1. UPLC-MS/MS was used to evaluate the in vitro and in vivo effects of apigenin on the uptake of acyclovir by OAT1. Cytotoxicity was determined by the cell viability, MTT assays. RESULTS: Apigenin effectively inhibited the activity of OAT1 in a dose-dependent manner with an IC50 value of 0.737µM. Pre-incubation of cells with apigenin caused a time-dependent inhibition (TDI) of OAT1. Additionally, we examined the interactions between apigenin and acyclovir or adefovir. Data showed that apigenin (1µM) significantly blocked the uptake of acyclovir by OAT1 in vitro with an inhibition rate of 55%. In vivo, apigenin could increase the concentration of acyclovir in plasma when co-administered with acyclovir. Importantly, the MTT assays showed that, at a dose of 50µM, apigenin significantly reduced the cytotoxicity of adefovir and substantially increased cell viability from 50.6% to 112.62%. CONCLUSION: Our results demonstrate that apigenin regulates OAT1, and can cause TDI or herb-drug interaction (HDI) when used in combination with acyclovir or adefovir. Therefore, apigenin could be used as a nephroprotective agent when used in combination with the substrates of OAT1.
Assuntos
Apigenina/farmacologia , Interações Ervas-Drogas , Nefropatias/prevenção & controle , Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores , Aciclovir/farmacocinética , Aciclovir/toxicidade , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/toxicidade , Animais , Antivirais/farmacocinética , Antivirais/toxicidade , Apigenina/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cães , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Nefropatias/induzido quimicamente , Células Madin Darby de Rim Canino , Masculino , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Organofosfonatos/farmacocinética , Organofosfonatos/toxicidade , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Fatores de TempoRESUMO
Since aminophosphonate-based herbicides like glyphosate are currently one of the most popular and widely applied active agent in agrochemistry, there is an urgent need for searching new compounds among this family with potential herbicidal activity, but exhibiting low toxicity against surrounding environment. Six new (5-nitrofurfuryl)-derived aminophosphonates were synthesized for the first time and apart from the only one example of N-benzylamino(5-nitrofuryl)-methylphosphonic acid, it was the first time in the history, when this class of compounds was prepared. Their prospective and real biological properties have been followed up by evaluation of their preliminary ecotoxicology. They have been then investigated in aspect of their phytotoxicity against oat (A. sativa) and common radish (R. sativus) exhibiting moderate-to-severe toxicity for these plants. The significant selectivity towards radish (up to 3 times greater toxicity against radish) was observed in some cases. Title compounds were also tested in terms of their toxicity for freshwater crustaceans H. incongruens (ostracods) and marine luminescent bacteria A. fischeri. Although their harmful action on ostracods was not too much elevated, they were found to be highly toxic for bacteria. Various aspects of their ecotoxicity are discussed in this paper.