Predicting the structures of metabolites formed in humans can provide advantageous insights for the development of drugs and other compounds. Here we present GLORYx, which integrates machine learning-based site of metabolism (SoM) prediction with reaction rule sets to predict and rank the structures of metabolites that could potentially be formed by phase 1 and/or phase 2 metabolism. GLORYx extends the approach from our previously developed tool GLORY, which predicted metabolite structures for cytochrome P450-mediated metabolism only. A robust approach to ranking the predicted metabolites is attained by using the SoM probabilities predicted by the FAME 3 machine learning models to score the predicted metabolites. On a manually curated test data set containing both phase 1 and phase 2 metabolites, GLORYx achieves a recall of 77% and an area under the receiver operating characteristic curve (AUC) of 0.79. Separate analysis of performance on a large amount of freely available phase 1 and phase 2 metabolite data indicates that achieving a meaningful ranking of predicted metabolites is more difficult for phase 2 than for phase 1 metabolites. GLORYx is freely available as a web server at https://nerdd.zbh.uni-hamburg.de/ and is also provided as a software package upon request. The data sets as well as all the reaction rules from this work are also made freely available.
- MeSH
- biotransformace * MeSH
- lidé MeSH
- molekulární struktura MeSH
- strojové učení * MeSH
- testy toxicity * MeSH
- xenobiotika chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Graphene oxide (GO) is an engineered nanomaterial which was demonstrated to have outstanding capacity for adsorption of organic pollutants such as polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), the ligands and activators of the aryl hydrocarbon receptor (AhR). Due to the partially overlapping ligand capacity of AhR and pregnane X receptor (PXR), we tested the impact of GO particles on their signalling. While reporter gene assay revealed potentiating effect of GO on ligand-activated AhR-dependent luciferase activity, there was no effect for PXR. However, inducible target genes for AhR (CYP1A1) or PXR (ABCB1) were decreased at mRNA as well as protein levels by the presence of GO in HepG2 (for AhR), LS180 (for PXR) or primary human hepatocytes (both receptors). Moreover, the presence of GO diminished PXR and AhR protein levels in primary cultures of human hepatocytes. This was partially reversed by proteasome inhibitor MG132 for AhR but not for PXR. In conclusion, GO decreases ligand-stimulated activities of AhR and PXR in human cells.
- MeSH
- biotransformace MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- grafit chemie MeSH
- hepatocyty účinky léků MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- pregnanový X receptor MeSH
- receptory aromatických uhlovodíků metabolismus MeSH
- reportérové geny MeSH
- signální transdukce MeSH
- steroidní receptory genetika MeSH
- xenobiotika chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This paper describes a potential environmental problem closely linked with the global production of water-soluble polymers such as polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). Both polymers make up the components of a multitude of products commonly utilized by industries and households. Hence, such a widespread use of PVA and PVP in the industrial sector and among consumers (the concentration of PVP in urban wastewater is approximately 7 mg/L) could pose a considerable problem, particularly to the environment. To this end, many publications have recently highlighted the poor biodegradability of PVA, in principle influenced by numerous biotic and abiotic factors. Facts published on the environmental fate of PVP have been scant, basically reporting that it is a biologically resistant polymer. As a result, the commercially produced water-soluble polymers of PVA and PVP are essentially non-biodegradable and possess the capacity to accumulate in virtually all environmental media. Consequently, there is a chance of heightened risk to the very environmental constituents in which PVA and PVP accumulate, depending on the routes of entry and transformation processes underway in such constituents of the ecosystem. This assumption is confirmed by the findings of initial research, which is worrying. Herein, PVA was detected in a soil environment, while a relatively high concentration of PVP was found in river water. A review of the literature was conducted to summarize the current state of knowledge concerning the fate of PVA and PVP in various environments, thereby also discerning potential solutions to tackle such dangers. This paper proposes methods to enhance the biodegradability of materials containing such materials; for PVA this means utilizing a suitable polysaccharide, whereas for PVP this pertains to actuating applications that induce substances to degrade. Accordingly, while it is understandable that this work cannot fully address all the issues associated with polymeric xenobiotics, it can still serve as a guide to discerning an economically viable solution, and provide a foundation for further research.
We report on the further development of FAst MEtabolizer (FAME; J. Chem. Inf. MODEL: 2013, 53, 2896-2907), a collection of random forest models for the prediction of sites of metabolism (SoMs) of xenobiotics. A broad set of descriptors was explored, from simple 2D descriptors such as those used in FAME, to quantum chemical descriptors employed in some of the most accurate models for SoM prediction currently available. In line with the original FAME approach, our objective was to keep things simple and to come up with accurate and robust models that are based on a small number of 2D descriptors. We found that circular descriptions of atoms and their environments with such descriptors in combination with an extremely randomized trees algorithm can yield models that perform equally well compared to more complex approaches. Thorough evaluation experiments on an independent test set showed that the best of these models obtained a Matthews correlation coefficient, area under the receiver operating characteristic curve, and Top-2 accuracy of 0.57, 0.91 and 94.1%, respectively. Models for the prediction of isoform-specific regioselectivity of CYP 3A4, 2D6, and 2C9 were also developed and showed competitive performance. The best models have been integrated into a newly developed software package (FAME 2), which is available free of charge from the authors.
Elimination or mitigation of the toxic effects of chemical waste released to the environment by industrial and urban activities relies largely on the catalytic activities of microorganisms-specifically bacteria. Given their capacity to evolve rapidly, they have the biochemical power to tackle a large number of molecules mobilized from their geological repositories through human action (e.g., hydrocarbons, heavy metals) or generated through chemical synthesis (e.g., xenobiotic compounds). Whereas naturally occurring microbes already have considerable ability to remove many environmental pollutants with no external intervention, the onset of genetic engineering in the 1980s allowed the possibility of rational design of bacteria to catabolize specific compounds, which could eventually be released into the environment as bioremediation agents. The complexity of this endeavour and the lack of fundamental knowledge nonetheless led to the virtual abandonment of such a recombinant DNA-based bioremediation only a decade later. In a twist of events, the last few years have witnessed the emergence of new systemic fields (including systems and synthetic biology, and metabolic engineering) that allow revisiting the same environmental pollution challenges through fresh and far more powerful approaches. The focus on contaminated sites and chemicals has been broadened by the phenomenal problems of anthropogenic emissions of greenhouse gases and the accumulation of plastic waste on a global scale. In this article, we analyze how contemporary systemic biology is helping to take the design of bioremediation agents back to the core of environmental biotechnology. We inspect a number of recent strategies for catabolic pathway construction and optimization and we bring them together by proposing an engineering workflow.
- MeSH
- Bacteria chemie genetika metabolismus MeSH
- biodegradace * MeSH
- biotechnologie trendy MeSH
- genetické inženýrství trendy MeSH
- látky znečišťující životní prostředí chemie toxicita MeSH
- lidé MeSH
- systémová biologie trendy MeSH
- xenobiotika chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Metabolic profile of mephedrone (4-methylmethcathinone, 4-MMC), a frequently abused recreational drug, was determined in rats in vivo. The urine of rats dosed with a subcutaneous bolus dose of 20mg 4-MMC/kg was analysed by LC/MS. Ten phase I and five phase II metabolites were identified by comparison of their retention times and MS(2) spectra with those of authentic reference standards and/or with the MS(2) spectra of previously identified metabolites. The main metabolic pathway was N-demethylation leading to normephedrone (4-methylcathinone, 4-MC) which was further conjugated with succinic, glutaric and adipic acid. Other phase I metabolic pathways included oxidation of the 4-methyl group, carbonyl reduction leading to dihydro-metabolites and ω-oxidation at the position 3'. Five of the metabolites detected, namely, 4-carboxynormephedrone (4-carboxycathinone, 4-CC), 4-carboxydihydronormephedrone (4-carboxynorephedrine, 4-CNE), hydroxytolyldihydro-normephedrone (4-hydroxymethylnorephedrine, 4-OH-MNE) and conjugates of 4-MC with glutaric and adipic acid, have not been reported as yet. The last two conjugates represent a novel, hitherto unexploited, type of phase II metabolites in mammals together with an analogous succinic acid conjugate of 4-MC identified by Pozo et al. (2015). These conjugates might be potentially of great importance in the metabolism of other psychoactive amines.
- MeSH
- adipáty metabolismus MeSH
- chromatografie kapalinová MeSH
- glutaráty metabolismus MeSH
- hmotnostní spektrometrie MeSH
- krysa rodu rattus MeSH
- kyselina jantarová metabolismus MeSH
- kyseliny dikarboxylové metabolismus MeSH
- metabolom MeSH
- methamfetamin analogy a deriváty chemie toxicita moč MeSH
- potkani Wistar MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- xenobiotika chemie toxicita moč MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
1. Purine cyclin-dependent kinase inhibitors have recently been recognised as promising candidates for the treatment of various cancers. While pharmacodynamic properties of these compounds are relatively well understood, their pharmacokinetics including possible interactions with placental transport systems have not been characterised to date. 2. In this study, we investigated transplacental passage of olomoucine II and purvalanol A in rat focusing on possible role of p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and/or multidrug resistance-associated proteins (ABCCs). Employing the in situ method of dually perfused rat term placenta, we demonstrate transplacental passage of both olomoucine II and purvalanol A against the concentration gradient in foetus-to-mother direction. Using several ATP-binding cassette (ABC) drug transporter inhibitors, we confirm the participation of ABCB1, ABCG2 and ABCCs transporters in the placental passage of olomoucine II, but not purvalanol A. 3. Transplacental passage of olomoucine II and purvalanol A from mother to foetus is significantly reduced by active transporters, restricting thereby foetal exposure and providing protection against harmful effects of these xenobiotics. Importantly, we demonstrate that in spite of their considerable structural similarity, the two molecules utilise distinct placental transport systems. These facts should be kept in mind when introducing these prospective anticancer candidates and/or their analogues into the clinical area.
- MeSH
- ABC transportéry metabolismus MeSH
- adenosintrifosfát chemie MeSH
- aktivní transport MeSH
- krysa rodu rattus MeSH
- matka - expozice noxám MeSH
- P-glykoproteiny metabolismus MeSH
- placenta účinky léků metabolismus MeSH
- potkani Wistar MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus MeSH
- puriny aplikace a dávkování farmakokinetika MeSH
- těhotenství u zvířat MeSH
- těhotenství MeSH
- trofoblasty účinky léků MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- xenobiotika chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Large amounts of biochar are produced worldwide for potential agricultural applications. However, this material can also be used as an efficient biosorbent for xenobiotics removal. In this work, biochar was magnetically modified using microwave-synthesized magnetic iron oxide particles. This new type of a magnetically responsive biocomposite material can be easily separated by means of strong permanent magnets. Magnetic biochar has been used as an inexpensive magnetic adsorbent for the removal of water-soluble dyes. Five dyes (malachite green, methyl green, Bismarck brown Y, acridine orange and Nile blue A) were used to study the adsorption process. The dyes adsorption could be usually described with the Langmuir isotherm. The maximum adsorption capacities reached the value 137 mg of dye per g of dried magnetically modified biochar for Bismarck brown Y. The adsorption processes followed the pseudo-second-order kinetic model and the thermodynamic studies indicated spontaneous and endothermic adsorption. Extremely simple magnetic modification of biochar resulted in the formation of a new, promising adsorbent suggested for selected xenobiotics removal.
The best known, most widely studied enzyme system in phase I biotransformation is cytochrome P450 (CYP), which participates in the metabolism of roughly 9 of 10 drugs in use today. The main biotransformation isoforms of CYP are associated with the membrane of the endoplasmatic reticulum (ER). Other enzymes that are also active in phase I biotransformation are carbonyl reducing enzymes. Much is known about the role of cytosolic forms of carbonyl reducing enzymes in the metabolism of xenobiotics, but their microsomal forms have been mostly poorly studied. The only well-known microsomal carbonyl reducing enzyme taking part in the biotransformation of xenobiotics is 11β-hydroxysteroid dehydrogenase 1, a member of the short-chain dehydrogenase/reductase superfamily. Physiological roles of microsomal carbonyl reducing enzymes are better known than their participation in the metabolism of xenobiotics. This review is a summary of the fragmentary information known about the roles of the microsomal forms. Besides 11β-hydroxysteroid dehydrogenase 1, it has been reported, so far, that retinol dehydrogenase 12 participates only in the detoxification of unsaturated aldehydes formed upon oxidative stress. Another promising group of microsomal biotransformation carbonyl reducing enzymes are some members of 17β-hydroxysteroid dehydrogenases. Generally, it is clear that this area is, overall, quite unexplored, but carbonyl reducing enzymes located in the ER have proven very interesting. The study of these enzymes could shed new light on the metabolism of several clinically used drugs or they could become an important target in connection with some diseases.
- MeSH
- 11-beta-hydroxysteroiddehydrogenasa typ 1 metabolismus MeSH
- 17-hydroxysteroidní dehydrogenasy metabolismus MeSH
- alkoholoxidoreduktasy metabolismus MeSH
- biotransformace MeSH
- endoplazmatické retikulum enzymologie MeSH
- katalýza MeSH
- kyseliny karboxylové chemie MeSH
- lidé MeSH
- mikrozomy enzymologie MeSH
- molekulární struktura MeSH
- oxidace-redukce MeSH
- substrátová specifita MeSH
- xenobiotika chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Magnetic techniques based on the application of magnetic nanoparticles and microparticles and films have been successfully used for the determination and detection of different types of xenobiotics (e.g. herbicides, insecticides, fungicides, aromatic and polyaromatic hydrocarbons, pentachlorophenol and heavy metal ions) as well as viruses, microbial pathogens and protozoan parasites in water samples. Preconcentration of xenobiotics from large volumes of samples can be performed using magnetic solid-phase extraction, stir-bar sorptive extraction and related procedures. This review provides basic information about these techniques. Published examples of successful applications document the importance of these simple and efficient procedures employing magnetic materials.
