Journal of Applied Toxicology
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Cytotoxic effects of psychotropic benzofuran derivatives,<i>N</i>-methyl-5-(2-aminopropyl)benzofuran and its<i>N</i>-demethylated derivative, on isolated rat hepatocytes
Journal of Applied Toxicology - Tập 37 Số 3 - Trang 243-252 - 2017
Preventive effects of fructose and <i>N</i>‐acetyl‐<scp>L</scp>‐cysteine against cytotoxicity induced by the psychoactive compounds <i>N</i>‐methyl‐5‐(2‐aminopropyl)benzofuran and 3,4‐methylenedioxy‐<i>N</i>‐methamphetamine in isolated rat hepatocytes Abstract Psychoactive compounds, N ‐methyl‐5‐(2‐aminopropyl)benzofuran (5‐MAPB) and 3,4‐methylenedioxy‐N ‐methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N ‐acetyl‐l ‐cysteine (NAC) on 5‐MAPB‐ and MDMA‐induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration‐dependent (0–4 mm ) and time‐dependent (0–3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH. The toxic effects of 5‐MAPB were greater than those of MDMA. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or NAC at a concentration of 2.5 mm prevented 5‐MAPB−/MDMA‐induced cytotoxicity. In addition, the exposure of hepatocytes to 5‐MAPB/MDMA caused the loss of mitochondrial membrane potential, although the preventive effect of fructose was weaker than that of NAC. These results suggest that: (1) 5‐MAPB−/MDMA‐induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were ameliorated, at least in part, by the addition of fructose; and (3) GSH loss via oxidative stress was prevented by NAC. Taken collectively, these results indicate that the onset of toxic effects caused by 5‐MAPB/MDMA may be partially attributable to cellular energy stress as well as oxidative stress.
Journal of Applied Toxicology - Tập 38 Số 2 - Trang 284-291 - 2018
<i>Benzo fur</i>y: A new trend in the drug misuse scene Abstract Benzofurans, also known by users as benzo fury or benzofury , are synthetic phenethylamines and constitute the third most prominent group of new psychoactive substances (NPS). As the use of these substances has been spread as an alternative to the classic illicit psychostimulants, such as amphetamines, their legal status was reviewed, resulting in an utter prohibition of these NPS in many countries worldwide. Herein, the prevalence of abuse, chemistry, biological effects, metabolism, and the potential harms and risky behaviors associated with the abuse of benzofurans are reviewed. The congeners of this group are mainly consumed recreationally at electronic dance music parties, in polydrug abuse settings. Benzofurans preferentially act by disturbing the functioning of serotonergic circuits, which induces their entactogenic and stimulant effects and is the reason behind the considerable number of recent benzo fury ‐related deaths. The slight interaction of these drugs with the dopaminergic system justifies the rewarding effects of these drugs. To date, published evidence on the mechanisms of toxicity of benzo fury is very limited but a body of research is now beginning to emerge revealing an alarming public health threat regarding the abuse of these NPS.
Journal of Applied Toxicology - Tập 39 Số 8 - Trang 1083-1095 - 2019
Anthraquinones inhibit cytochromes P450 enzyme activity in silico and in vitro Abstract Anthraquinones exhibit various pharmacological activities (e.g., antioxidant and laxative) and are commonly found in consumer products including foods, dietary supplements, drugs, and traditional medicines. Despite their widespread use, there are limited data available on their toxicokinetic properties. Cytochrome P450 enzymes (CYPs) in the liver play major roles in metabolizing exogenous chemicals (e.g., pharmaceuticals, food ingredients, and environmental pollutants) and endogenous biomolecules (e.g., steroid hormones and cholesterol). Inhibition of CYP activities may lead to serious interactions among these compounds. Here, in silico (quantitative structure‐activity relationship modeling) and in vitro (human recombinant enzymes and liver microsomes) methods were used to identify inhibitors of five major CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) among 22 anthraquinones. First, in silico prediction and in vitro human recombinant enzyme assays were conducted for all compounds, and results showed that most of the anthraquinones were potent CYP1A2 inhibitors. Second, five selected anthraquinones (emodin, aloe‐emodin, rhein, purpurin, and rubiadin) were further evaluated in human liver microsomes. Finally, plasma concentrations of the five anthraquinones in animal and humans were identified in the literature and compared to their in vitro inhibition potency (IC 50 values) towards CYP activities. Emodin, rhein, and aloe‐emodin inhibited activities of multiple CYPs in human liver microsomes and potential in vivo inhibition may occur due to their high plasma concentrations. These in silico and in vitro results enabled rapid identification of potential CYP inhibitors and prioritized future in‐depth studies.
Journal of Applied Toxicology - Tập 41 Số 9 - Trang 1438-1445 - 2021
Woodworkers' exposure to tannins Abstract The tannin concentration of hard‐ and soft‐wood dust was determined in dust powder and in samples on filters. It varied from 1.6 ± 0.3 mg g−1 (± SD) for fir, which is a soft wood, to 80 ± 30 mg g−1 (± SD) for oak, which is a hard wood. The low detection limit of the spectrophotometric method (1.5 μg per sample) made the analysis possible with no interference from cellulose ester filters. In five woodworking shops the concentrations of the total dust varied from 0.2 to 20 mg m−3 , while those of tannins varied from 2 to 341 μg m−3 . As hard woods like oak or mahogany have a higher tannin concentration than soft woods, tannin concentration analysis in wood dust can be used as an indicator of exposure to hard‐wood dust.
Journal of Applied Toxicology - Tập 14 Số 4 - Trang 293-295 - 1994
Potential developmental toxicity of anatoxin-a, a cyanobacterial toxin
Journal of Applied Toxicology - Tập 25 Số 6 - Trang 527-534 - 2005
Time‐dependent biodistribution and excretion of silver nanoparticles in male Wistar rats ABSTRACT Silver nanoparticles (AgNPs) are the most commonly used nanoparticles owing to their antimicrobial properties. The motivation of the present study was (1) to analyze the effect of silver particle size on rat tissue distribution at different time points, (2) to determine the accumulation of AgNPs in potential rat target organs, (3) to analyze the intracellular distribution of AgNPs and (4) to examine the excretion of AgNPs by urine and feces. AgNPs were characterized by dynamic light scattering (DLS), zeta potential measurements, BET surface area measurements, transmission and scanning electron microscopy. AgNPs (20 and 200 nm) were administered intravenously (i.v.) to male Wistar rats at a dose of 5 mg kg–1 of body weight. Biological material was sampled 24 h, 7 and 28 days after injection. Using inductively coupled plasma‐mass spectrometry (ICP‐MS) and transmission electron microscopy (TEM) it was observed that AgNPs translocated from the blood to the main organs and the concentration of silver in tissues was significantly higher in rats treated with 20 nm AgNPs as compared with 200 nm AgNPs. The highest concentration of silver was found in the liver after 24 h. After 7 days, a high level of silver was observed in the lungs and spleen. The silver concentration in the kidneys and brain increased during the experiment and reached the highest concentration after 28 days. Moreover, the highest concentration of AgNPs was observed in the urine 1 day after the injection, maintained high for 14 days and then decreased. The fecal level of silver in rats was the highest within 2 days after AgNPs administration and then decreased. Copyright © 2012 John Wiley & Sons, Ltd.
Journal of Applied Toxicology - Tập 32 Số 11 - Trang 920-928 - 2012
Influence of the surface coating on the cytotoxicity, genotoxicity and uptake of gold nanoparticles in human HepG2 cells ABSTRACT The toxicological profile of gold nanoparticles (AuNPs) remains controversial. Significant efforts to develop surface coatings to improve biocompatibility have been carried out. In vivo biodistribution studies have shown that the liver is a target for AuNPs accumulation. Therefore, we investigated the effects induced by ~20 nm spherical AuNPs (0–200 μM Au) with two surface coatings, citrate (Cit) compared with 11‐mercaptoundecanoic acid (11‐MUA), in human liver HepG2 cells. Cytotoxicity was evaluated using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release assays after 24 to 72 h of incubation. DNA damage was assessed by the comet assay, 24 h after incubation with the capped AuNPs. Uptake and subcellular distribution of the tested AuNPs was evaluated by quantifying the gold intracellular content by graphite furnace atomic absorption spectrometry (GFAAS) and transmission electron microscopy (TEM), respectively. The obtained results indicate that both differently coated AuNPs did not induce significant cytotoxicity. An inverse concentration‐dependent increase in comet tail intensity and tail moment was observed in Cit‐AuNPs‐ but not in MUA‐AuNPs‐exposed cells. Both AuNPs were internalized in a concentration‐dependent manner. However, no differences were found in the extent of the internalization between the two types of NPs. Electron‐dense deposits of agglomerates of Cit‐ and MUA‐AuNPs were observed either inside endosomes or in the intercellular spaces. In spite of the absence of cytotoxicity, DNA damage was observed after exposure to the lower concentrations of Cit‐ but not to MUA‐AuNPs. Thus, our data supports the importance of the surface properties to increase the biocompatibility and safety of AuNPs. Copyright © 2013 John Wiley & Sons, Ltd.
Journal of Applied Toxicology - Tập 33 Số 10 - Trang 1111-1119 - 2013
Activation of the <i>N</i>‐methyl‐<scp>d</scp>‐aspartate receptor is involved in glyphosate‐induced renal proximal tubule cell apoptosis Abstract Glyphosate‐based herbicides have been used worldwide for decades and have been suggested to induce nephrotoxicity, but the underlying mechanism is not yet clear. In this study, we treated a human renal proximal tubule cell line (HK‐2) with glyphosate for 24 hours at concentrations of 0, 20, 40 and 60 μm . Glyphosate was found to reduce cell viability and induce apoptosis and oxidative stress in a dose‐dependent manner. Because the chemical structures of glyphosate and those of its metabolite AMPA are similar to glycine and glutamate, which are agonists of the N ‐methyl‐d ‐aspartate receptor (NMDAR), we investigated the potential role of the NMDAR pathway in mediating the proapoptotic effect of glyphosate on proximal tubule cells. We found that NMDAR1 expression, as well as intracellular Ca2+ ([Ca2+ ]i ) and reactive oxygen species (ROS) levels, increased after glyphosate treatment. Blocking NMDAR attenuated glyphosate‐induced upregulation of [Ca2+ ]i and ROS levels as well as apoptosis. Meanwhile, inhibition of [Ca2+ ]i reduced glyphosate‐induced ROS and apoptosis, and inhibition of ROS alleviated glyphosate‐induced apoptosis. In mice exposed to 400 mg/kg glyphosate, the urine low molecular weight protein levels started to increase from day 7. Upregulation of apoptosis and NMDAR1 expression in renal proximal tubule epithelium and an imbalance of oxidant and antioxidative products were observed. These results strongly suggest that activation of the NMDAR1 pathway, together with its downstream [Ca2+ ]i and oxidative stress, is involved in glyphosate‐induced renal proximal tubule epithelium apoptosis.
Journal of Applied Toxicology - Tập 39 Số 8 - Trang 1096-1107 - 2019
Adverse effect of FTY720P on colonic Na<sup>+</sup>/K<sup>+</sup> ATPase is mediated via ERK, p38MAPK, PKC, and PI3K Abstract FTY720P, an analogue of sphingosine 1‐phosphate, has emerged lately as a potential causative agent of inflammatory bowel disease, in which electrolytes movements driven by the sodium gradient established by the Na+ /K+ ATPase are altered. We showed previously in Caco‐2 cells, a 50% FTY720P‐induced decrease in the ATPase activity, mediated via S1PR2 and PGE2. This work aims at delineating the mechanism underlying PGE2 release and at investigating if the ATPase inhibition is due to changes in its abundance. The activity of the ATPase and the localization of a GFP‐tagged Na+ /K+ ‐ATPase α1 ‐subunit were assessed in cells treated with 7.5 nM FTY720P. The involvement of ERK, p38 MAPK, PKC, and PI3K was studied in cells treated with 7.5 nM FTY720P or 1 nM PGE2 in presence of their inhibitors, or by determining changes in the protein expression of their activated phosphorylated forms. Imaging data showed ∼30% reduction in the GFP‐tagged Na+ /K+ ATPase at the plasma membrane. Both FTY720P and PGE2 showed, respectively, 50% and 60% reduction in ATPase activity that disappeared when p38 MAPK, PKC, and PI3K were inhibited individually but not with ERK inhibition. The effect of FTY720P was imitated by PMA, an activator of PKC. Western blotting revealed inhibition of ERK by FTY720P. It was concluded that FTY720P, through activation of S1PR2, downregulates the Na+ /K+ ATPase by inhibiting ERK, which in turn activates p38 MAPK leading to the sequential activation of PKC and PI3K, PGE2 release, and a decrease in the Na+ /K+ ATPase activity and membrane abundance.
Journal of Applied Toxicology - Tập 43 Số 2 - Trang 220-229 - 2023
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