Mehanizmi delovanja tveganih kemijskih struktur za mutagenost in kancerogenost

Knowing the mutagenic and carcinogenic properties of chemicals is very important for their hazard (and risk) assessment. One of the crucial events that trigger genotoxic and sometimes carcinogenic effects is the forming of adducts between chemical compounds and nucleic acids and histones. This review takes a look at the mechanisms related to specific functional groups (structural alerts or toxicophores) that may trigger genotoxic or epigenetic effects in the cells. We present up-to-date information about defined structural alerts with their mechanisms and the software based on this knowledge (QSAR models and classification schemes).Poznavanje mutagenih in rakotvornih lastnosti kemikalij je zelo pomembno za njihovo oceno tveganja in nevarnosti. Eden od ključnih dogodkov, ki sprožijo genotoksični in včasih kancerogeni učinkek je tvorba aduktov med kemikalijami in nukleinskimi kislinami ter histoni. Ta članek povzema pregled mehanizmov povezanih s specifičnimi funkcionalnimi skupinami (strukturnimi alerti ali tveganimi kemijskimi strukturami), ki lahko sprožijo genotoksične ali epigenetske učinke v celicah. Predstavlja aktualne informacije o poznanih strukturnih alertih, njihove mehanizme interakcij z genetskim materialom in programsko opremo, ki na osnovi poznavanja teh mehanizmov z uporabo QSAR modelov in klasifikacijskih shem omogočajo napovedovanje genostoksičnosti še nepoznanih kemikalij

Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors

DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 mu M for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Grampositive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 mu M. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV. (C) 2017 Elsevier Masson SAS. All rights reserved.Peer reviewe

Computational study of drugs targeting nuclear receptors

Endocrine-disrupting chemicals have been shown to interfere with the endocrine system function at the level of hormone synthesis, transport, metabolism, binding, action, and elimination. They are associated with several health problems in humans: obesity, diabetes mellitus, infertility, impaired thyroid and neuroendocrine functions, neurodevelopmental problems, and cancer are among them. As drugs are chemicals humans can be frequently exposed to for longer periods of time, special emphasis should be put on their endocrine-disrupting potential. In this study, we conducted a screen of 1046 US-approved and marketed small-molecule drugs (molecular weight between 60 and 600) for estimating their endocrine-disrupting properties. Binding affinity to 12 nuclear receptors was assessed with a molecular-docking program, Endocrine Disruptome. We identified 130 drugs with a high binding affinity to a nuclear receptor that is not their pharmacological target. In a subset of drugs with predicted high binding affinities to a nuclear receptor with Endocrine Disruptome, the positive predictive value was 0.66 when evaluated with in silico results obtained with another molecular docking program, VirtualToxLab, and 0.32 when evaluated with in vitro results from the Tox21 database. Computational screening was proven useful in prioritizing drugs for in vitro testing. We suggest that the novel interactions of drugs with nuclear receptors predicted here are further investigated

Predictive models for compound binding to androgen and estrogen receptors based on counter-propagation artificial neural networks

Endocrine-disrupting chemicals (EDCs) are exogenous substances that interfere with the normal function of the human endocrine system. These chemicals can affect specific nuclear receptors, such as androgen receptors (ARs) or estrogen receptors (ER) α and β, which play a crucial role in regulating complex physiological processes in humans. It is now more crucial than ever to identify EDCs and reduce exposure to them. For screening and prioritizing chemicals for further experimentation, the use of artificial neural networks (ANN), which allow the modeling of complicated, nonlinear relationships, is most appropriate. We developed six models that predict the binding of a compound to ARs, ERα, or ERβ as agonists or antagonists, using counter-propagation artificial neural networks (CPANN). Models were trained on a dataset of structurally diverse compounds, and activity data were obtained from the CompTox Chemicals Dashboard. Leave-one-out (LOO) tests were performed to validate the models. The results showed that the models had excellent performance with prediction accuracy ranging from 94% to 100%. Therefore, the models can predict the binding affinity of an unknown compound to the selected nuclear receptor based solely on its chemical structure. As such, they represent important alternatives for the safety prioritization of chemicals

Effects of central nervous system drugs on androgen, estrogen α, glucocorticoid, and thyroid receptors

Some drugs that act on the central nervous system (CNS) are known to affect the endocrine system, although the mechanisms of endocrine toxicity are not well characterized to date. Such CNS drugs include antipsychotics, anticonvulsants, and antidepressants. In the present study, in-vitro firefly luciferase reporter-gene assays using the AR-EcoScreen assay using Chinese hamster ovary (CHO) cell line, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cell lines were used to determine the effects of nine CNS drugs on the androgen receptor, estrogen receptor α, glucocorticoid receptor, and thyroid hormone receptor, respectively. In the AR-EcoScreen assay using CHO cells, anti-androgenic activities were shown for carbamazepine (IC$_{50}$, 167 μM), clonazepam (IC$_{50}$, 26.7 μM), eslicarbazepine acetate (IC$_{50}$, 375 μM), fluoxetine (at 25 μM), lorazepam (IC$_{50}$, 16.4 μM), and sertraline (IC$_{50}$, 8.7 μM). In the hERα-HeLa-9903 cells, estrogen receptor α agonistic activities were shown for fluoxetine, paroxetine, and sertraline (at 10 μM and 25 μM), and in the GH3.TRE-Luc cells, the same three CNS drugs showed antithyroid activities (IC$_{50}$s, 11.6, 11.9, 2.7 μM, respectively). In the hERα-HeLa-9903 cells, estrogen receptor α antagonistic activities were shown for carbamazepine (IC$_{50}$, 114.3 μM), clonazepam (IC$_{50}$, 52.9 μM), and eslicarbazepine acetate (IC$_{50}$, 376.6 μM). When the CNS drugs were tested in the MDA-kb2 cells, none of them showed any activities toward glucocorticoid receptors. Little to no effects were seen toward any of these nuclear receptors for paliperidone and risperidone. The increased signal in the estrogen receptor α agonism assay seen for fluoxetine and paroxetine was confirmed to be mediated through estrogen receptor α. Additionally, we examined the interference of these CNS drugs with the firefly luciferase enzyme. These data elucidate the potential for adverse endocrine effects for some of these CNS drugs, which should therefore contribute to informed choice when prescribing them. However, long-term exposure to therapeutic concentrations of CNS drugs that have activities on the endocrine system should be explored further also in vivo

A review on immunomodulatory effects of BPA analogues

Bisphenol A (BPA) is a known endocrine disruptor found in many consumer products that humans come into contact with on a daily basis. Due to increasing concerns about the safety of BPA and the introduction of new legislation restricting its use, industry has responded by adopting new, less studied BPA analogues that have similar polymer-forming properties. Some BPA analogues have already been shown to exhibit effects similar to BPA, for example, contributing to endocrine disruption through agonistic or antagonistic behaviour at various nuclear receptors such as estrogen (ER), androgen (AR), glucocorticoid (GR), aryl hydrocarbon (AhR), and pregnane X receptor (PXR). Since the European Food Safety Authority (EFSA) issued a draft re-evaluation of BPA and drastically reduced the temporary tolerable daily intake (t-TDI) of BPA from 4 mg/kg body weight/day to 0.2 ng/kg body weight/day due to increasing concern about the toxic properties of BPA, including its potential to disrupt immune system processes, we conducted a comprehensive review of the immunomodulatory activity of environmentally abundant BPA analogues. The results of the review suggest that BPA analogues may affect both the innate and acquired immune systems and can contribute to various immune-mediated conditions such as hypersensitivity reactions, allergies, and disruption of the human microbiome

Development of in silico classification models for binding affinity to the glucocorticoid receptor

The endocrine disrupting properties of chemicals acting through the glucocorticoid receptor (GR) have attracted considerable interest. Since there are few data for most chemicals on their endocrine properties in silico approaches seem to be the most appropriate tool for screening and prioritizing chemicals for planning further experiments. In this work, we developed classification models for binding affinity to the glucocorticoid receptor using the counterpropagation artificial neural network method. We considered two series of 142 and 182 compounds and their binding affinity to the glucocorticoid receptor as agonists and antagonists, respectively. The compounds belong to different chemical classes. The compounds were represented by a set of descriptors calculated with the DRAGON program. The clustering structure of sets was studied with standard principal component method. A weak separation between binders and non-binders was found. Another classification model was developed using the counterpropagation artificial neural network method (CPANN). The final classification models developed were well balanced and showed a high level of accuracy, with 85.7% of GR agonist and 78.9% of GR antagonist correctly assigned in leave-one-out cross-validation

Medicinal plants used for anxiety, depression, or stress treatment

Depression, anxiety, stress, and other mental disorders, which are on the rise worldwide, are indications that pharmacological therapy can have serious adverse effects, which is why many patients prefer to use herbal products to treat these symptoms. Here, we reviewed plants and products derived from them that are commonly used for the above indications, focusing on clinical data and safety profiles. While lavender, hops, maypop, lemon balm, and valerian have consistently been shown in clinical trials to relieve mild forms of neurological disorders, particularly depression, anxiety, and stress, currently available data do not fully support the use of peppermint for anxiety disorders and depression. Recent studies support the use of saffron for depressionhowever, its toxicological profile raises safety concerns. St. John’s wort is effective in alleviating mild to moderate depressionhowever, careful use is necessary particularly due to possible interactions with other drugs. In conclusion, more studies are needed to validate the mechanism of action so that these plants can be used successfully and safely to alleviate or eliminate various mental disorders

Mutagenost in poškodbe DNA povzročene z bisfenolom A in njegovimi strukturnimi analogi v celični liniji HEPG2

Environmental oestrogen bisphenol A (BPA) and its analogues are widespread in our living environment. Because their production and use are increasing, exposure of humans to bisphenols is becoming a significant issue. We evaluated the mutagenic and genotoxic potential of eight BPA structural analogues (BPF, BPAF, BPZ, BPS, DMBPA, DMBPS, BP-1, and BP-2) using the Ames and comet assay, respectively. None of the tested bisphenols showed a mutagenic effect in Salmonella typhimurium strains TA98 and TA100 in either the presence or absence of external S9-mediated metabolic activation (Aroclor 1254-induced male rat liver). Potential genotoxicity of bisphenols was determined in the human hepatoma cell line (HepG2) at non-cytotoxic concentrations (0.1 μmol L-1 to 10 μmol L-1) after 4-hour and 24-hour exposure. In the comet assay, BPA and its analogue BPS induced signifi cant DNA damage only after the 24-hour exposure, while analogues DMBPS, BP-1, and BP-2 induced a transient increase in DNA strand breaks observed only after the 4-hour exposure. BPF, BPAF, BPZ, and DMBPA did not induce DNA damage.Ker njihova proizvodnja in uporaba naraščata, je vse pomembneje ovrednotiti njihovo toksičnost zaradi izpostavljenosti ljudem. Z Amesovim in kometnim testom smo ovrednotili mutagenost in genotoksičnost osmih strukturnih analogov BPA (BPF, BPAF, BPZ, BPS, DMBPA, DMBPS, BP-1 in BP-2). Nobeden od testiranih bisfenolov ni izkazoval mutagenega delovanja na sevih TA98 in TA100 Salmonelle tryhimurium v prisotnosti in odsotnosti metabolne aktivacije (z Aroklorom 1254 inducirani encimi podganjih jeter). Potencialno genotoksičnost pa smo določali s kometnim testom na celični liniji humanega hepatoma (HepG2) pri necitotoksičnih koncentracijah (0.1 μmol L-1 do 10 μmol L-1) po 4-urni in 24-urni izpostavljenosti. BPA in njegov analog BPS sta pri kometnem testu povzročila poškodbe DNA samo po 24-urni izpostavljenosti, medtem ko so analogi DMBPS, BP-1 in BP-2 povzročili prehodne poškodbe DNA (samo po 4-urni izpostavljenosti). BPF, BPAF, BPZ in DMBPA niso povzročili poškodb DNA