A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically infl...
Mitoxantrone (MTX) is an antitumor agent that causes cardiotoxicity in 18 % patients. The metabolic profile of MTX was assessed after incubation of 100 lM MTX with hepatic S9 fraction isolated from rats. The presence of MTX and its metabolites was also assessed in vivo through the analysis of liver and heart extracts of MTX-treated rats. The cytotoxic effects of MTX and MTX metabolites were evaluated in the H9c2 cells after 24-h incubation with MTX alone and MTX ? metabolites. The influence of CYP450-and CYP2E1-mediated metabolism for the cytotoxicity of MTX was assessed after 96-h incubation with MTX (100 nM and 1 lM) in the presence/ absence of CYP450 or CYP2E1 inhibitors. After 4-h incubation in supplemented S9 fraction, the MTX content was 35 % lower and 5 metabolites were identified: an acetoxy ester derivative (never described before), two glutathione conjugates, a monocarboxylic acid derivative, and the naphtoquinoxaline, the later commonly related to MTX pharmacological effects. The presence of MTX and naphtoquinoxaline metabolite was evidenced in vivo in liver and heart of MTX-treated rats. The cytotoxicity caused by MTX ? metabolites was higher than that observed in the H9c2 cells incubated with non-metabolized MTX group. The co-incubation of MTX with CYP450 and CYP2E1 inhibitors partially prevented the cytotoxicity observed in the MTX groups incubated with H9c2 cells, highlighting that the metabolism of MTX is relevant for its undesirable effects. The naphtoquinoxaline metabolite is described in heart and liver in vivo, highlighting that this metabolite accumulates in these tissues. It was demonstrated that MTX P450-mediated metabolism contributed to MTX toxicity.
Abuse of synthetic drugs is widespread among young people worldwide. In this context, piperazine derived drugs recently appeared in the recreational drug market. Clinical studies and case-reports describe sympathomimetic effects including hypertension, tachycardia, and increased heart rate. Our aim was to investigate the cytotoxicity of N-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1-(4-methoxyphenyl) piperazine (MeOPP), and 1-(3,4-methylenedioxybenzyl) piperazine (MDBP) in the H9c2 rat cardiac cell line. Complete cytotoxicity curves were obtained at a 0-20 mM concentration range after 24 h incubations with each drug. The EC50 values (μM) were 343.9, 59.6, 570.1, and 702.5 for BZP, TFMPP, MeOPP, and MDBP, respectively. There was no change in oxidative stress markers. However, a decrease in total GSH content was noted for MDBP, probably due to metabolic conjugation reactions. All drugs caused significant decreases in intracellular ATP, accompanied by increased intracellular calcium levels and a decrease in mitochondrial membrane potential that seems to involve the mitochondrial permeability transition pore. The cell death mode revealed early apoptotic cells and high number of cells undergoing secondary necrosis. Among the tested drugs, TFMPP seems to be the most potent cytotoxic compound. Overall, piperazine designer drugs are potentially cardiotoxic and support concerns on risks associated with the intake of these drugs.
This review aimed to investigate possible protective or deleterious effects of polyphenol-rich foods (PRF) on chronic diseases, e.g. cardiovascular, and in pregnant women, along with their antioxidant and anti-inflammatory action. A great variety of foods and beverages, such as herbal teas, grape and orange derivatives, dark chocolate, and many others contain high concentrations of flavonoids and are freely consumed by the general population. In humans, PRF consumption reduces lipid peroxidation, and several studies have shown a positive correlation between an increased consumption of PRF and a decrease in the incidence of cardiovascular disease. On the other hand, current studies have suggested that maternal ingestion of PRF, especially during the third trimester of pregnancy, could be associated to fetal ductal constriction (DC). Fetuses exposed to this type of diet show higher ductal velocities and lower pulsatility indexes, as well as larger right ventricles than those exposed to minimal amounts of these substances. The underlying mechanism involved in these conditions has not been entirely elucidated, but it seems to be a result of the antioxidant and anti-inflammatory effects of polyphenols by some pathway. Furthermore, taking into account the deleterious effect in late-pregnancy against the numerous positive effects associated to polyphenols, this dual behavior deserves attention particularly to control the dietary ingestion of PRF during gestation. In this line, same PRF, natural constituents of human diet, may represent risk to fetal in late pregnancy compared to the use of nonsteroidal anti-inflammatory drugs.
N-acetylcysteine (NAC) is a potent mucolitic agent and also an antioxidant. Its antioxidant action is due to its ability to stimulate reduced glutathione (GSH) synthesis, therefore maintaining intracellular levels. The aim of this study was to evaluate the effects of NAC administered intraperitoneally (i.p.) in a decreasing of oxidative tissue damage in the liver and kidney of alloxan-induced diabetic rats, especially on thiolic groups (nonproteic and proteic groups). Adult male Wistar rats (200-350 g) were used; diabetes was induced accordingly by a single i.p. injection of alloxan monohydrate, and the control group received a similar volume of the vehicle. Lipid peroxidation (LPO) biomarker (malondialdehyde; MDA), δ-ALA-D activity, GSH, superoxide dismutase (SOD), and glutathione peroxidase (GPx) were quantified to assess the oxidative stress. All tests were performed in tissue homogenates. Creatinine, urea, aspartate transaminase, and alanine transaminase were determined by commercial kits, using serum samples. A significant decrease in LPO (i.e., hepatic and renal) and an increase in δ-aminolevulinate dehydratase activity, especially in the renal tissue, were observed. Also, NAC at 75 mg/kg showed more effective restoration of oxidative stress biomarkers than NAC at 25 mg/kg. Our findings suggest that NAC can be used as an antioxidant agent in diabetes, exhibiting modulatory action on the oxidative stress biomarkers analyzed in this work. Moreover, these findings can contribute to others' research, regarding the utilization of NAC to ALA-D activity restoration in the kidneys.
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