Chemical Research in Toxicology最新文献

Bromo-DragonFLY is a synthetic new psychoactive substance (NPS) that has gained attention due to its powerful and long-lasting hallucinogenic effects, legal status, and widespread availability. This study aimed to use various in silico toxicology methods to predict key toxicological parameters for Bromo-DragonFLY, including acute toxicity (LD₅₀), genotoxicity, cardiotoxicity, health effects, and the potential for endocrine disruption. The results indicate significant acute toxicity with noticeable variations across different species, a low likelihood of genotoxic potential suggesting potential DNA damage, and a notable risk of cardiotoxicity associated with inhibition of the hERG channel. Evaluation of endocrine disruption suggests a low probability of Bromo-DragonFLY interacting with the estrogen receptor α (ER-α), indicating minimal estrogenic activity. These insights from in silico investigations are important for advancing our understanding of this NPS in forensic and clinical toxicology. These initial toxicological examinations establish a foundation for future research efforts and contribute to developing risk assessment and management strategies for using and misusing NPS.

The oxidation of proteins and, in particular, of tryptophan (Trp) residues leads to chemical modifications that can affect the structure and function. The oxidative damage to proteins in photochemical processes is relevant in the skin and eyes and is related to a series of pathologies triggered by exposure to electromagnetic radiation. In this work, we studied the photosensitized formation of N-formylkynurenine (NFKyn) from Trp in different reaction systems. We used two substrates: free Trp and a peptide of nine amino acid residues, with Trp being the only oxidizable residue. Two different photosensitizers were employed: Rose Bengal (RB) and pterin (Ptr). The former is a typical type II photosensitizer [acts by producing singlet oxygen (¹O₂)]. Ptr is the parent compound of oxidized or aromatic pterins, natural photosensitizers that accumulate in human skin under certain pathological conditions and act mainly through type I mechanisms (generation of radicals). Experimental data were collected in steady photolysis, and the irradiated solutions were analyzed by chromatography (HPLC). Results indicate that the reaction of Trp with ¹O₂ initiates the process leading to NFKyn, but different competitive pathways take place depending on the photosensitizer and the substrate. In Ptr-photosensitization, a type I mechanism is involved in secondary reactions accelerating the formation of NFKyn when free Trp is the substrate.

This study introduces a novel cheminformatic read-across approach designed to identify potential environmental obesogens, substances capable of disrupting metabolism and inducing obesity by mainly influencing nuclear hormone receptors (NRs). Leveraging real-valued two-dimensional features derived from chemical fingerprints of 8435 Tox21 compounds, cluster analysis and subsequent statistical testing revealed 385 clusters enriched with compounds associated with specific NR targets. Notably, one cluster exhibited selective enrichment in peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, prominently featuring methoxy cinnamate ultraviolet (UV) filters and obesogen-related compounds. Experimental validation confirmed that 2-ethoxyethyl 4-methoxycinnamate, an organic UV filter cinoxate, could selectively bind to PPARγ (K_i = 18.0 μM), eliciting an obesogenic phenotype in human bone marrow-derived mesenchymal stem cells during adipogenic differentiation. Molecular docking and further experiments identified cinoxate as a potent PPARγ full agonist, demonstrating a preference for coactivator SRC3 recruitment. Moreover, cinoxate upregulated transcription levels of genes encoding lipid metabolic enzymes in normal human epidermal keratinocytes as primary cells exposed during clinical usage. This study provides compelling evidence for the efficacy of cheminformatic read-across analysis in prioritizing potential obesogens, showcasing its utility in unveiling cinoxate as an obesogenic PPARγ agonist.

Reactive metabolite (RM) formation is widely accepted as playing a crucial role in causing idiosyncratic adverse drug reactions (IADRs), where the liver is most affected. An important goal of drug design is to avoid selection of drug candidates giving rise to RMs and therefore risk causing problems later on involving IADRs. The simplest, initial approach is to avoid test structures that have substructures known or strongly suspected to be associated with IADRs. However, as is evident from the many case reports of IADRs, in most cases a clear association with any (bio)chemical mechanism is lacking, which makes it hard to establish any structure-toxicity relationship. Separate studies of RM formation, in vitro and in vivo, have led to likely evidence and to establishing many structural alerts (SAs) that can be used for fast selection/deselection of planned test compounds. As a background to a discussion of the concept, 25 kinase inhibitor drugs with known problems of hepatotoxicity were probed against a set of SAs contained in the application SpotRM. A clear majority of the probed drugs show liabilities as evident by being flagged by more than one of the fairly established types of SAs. At the same time, no clear SAs were found in three drugs, which is discussed in the broader context of usefulness and selection tactics of SAs in drug design.

Nicotine salt-based e-liquids deliver nicotine more rapidly and efficiently to electronic nicotine delivery system (ENDS) users than freebase nicotine formulations. Nicotine salt-based products represent a substantial majority of the United States ENDS market. Despite the popularity of nicotine salt formulations, the chemical and physical characteristics of aerosols produced by nicotine salt e-liquids are still not well understood. To address this, this study reports the harmful and potentially harmful constituents (HPHCs) and particle sizes of aerosols produced by laboratory-made freebase nicotine and nicotine salt e-liquids. The nicotine salt e-liquids were formulated with benzoic acid, citric acid, lactic acid, malic acid, or oxalic acid. The nicotine salt aerosols had different HPHC profiles than the freebase nicotine aerosols, indicating that the carboxylic acids were not innocent bystanders. The polycarboxylic acid e-liquids containing citric acid, malic acid, or oxalic acid produced higher acrolein yields than the monocarboxylic acid e-liquids containing benzoic acid or lactic acid. Across most PG:VG ratios, nicotine benzoate or nicotine lactate aerosols contained the highest nicotine quantities (in %) and the highest nicotine yields (per milligram of aerosol). Additionally, the nicotine benzoate and nicotine lactate e-liquids produced the highest carboxylic acid yields under all tested conditions. The lower acid yields of the citric, malic, and oxalic acid formulations are potentially due to a combination of factors such as lower transfer efficiencies, lower thermostabilities, and greater susceptibility to side reactions because of their additional carboxyl groups serving as new sites for reactivity. For all nicotine formulations, the particle size characteristics were primarily controlled by the e-liquid solvent ratios, and there were no clear trends between nicotine salt and freebase nicotine aerosols that indicated nicotine protonation affected particle size. The carboxylic acids impacted aerosol output, nicotine delivery, and HPHC yields in distinct ways such that interchanging them in ENDS can potentially cause downstream effects.

The outbreak of e-cigarette or vaping use-associated lung injury (EVALI) in the United States in 2019 led to a total of 2807 hospitalizations with 68 deaths. While the exact causes of this vaping-related lung illness are still being debated, laboratory analyses of products from victims of EVALI have shown that vitamin E acetate (VEA), an additive in some tetrahydrocannabinol (THC)-containing products, is strongly linked to the EVALI outbreak. Because of its similar appearance and viscosity to pure THC oil, VEA was used as a diluent agent in cannabis oils in illicit markets. A potential mechanism for EVALI may involve VEA’s thermal decomposition product, ketene, a highly poisonous gas, being generated under vaping conditions. In this study, a novel approach was developed to evaluate ketene production from VEA vaping under measurable temperature conditions in real-world devices. Ketene in generated aerosols was captured by two different chemical agents and analyzed by gas chromatography–mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). The LC-MS/MS method takes advantage of the high sensitivity and specificity of tandem mass spectrometry and appears to be more suitable than GC-MS for the analysis of large batches of samples. Our results confirmed the formation of ketene when VEA was vaped. The production of ketene increased with repeat puffs and showed a correlation to temperatures (200 to 500 °C) measured within vaping devices. Device battery power strength, which affects the heating temperature, plays an important role in ketene formation. In addition to ketene, the organic oxidant duroquinone was also obtained as another thermal degradation product of VEA. Ketene was not detected when vitamin E was vaped under the same conditions, confirming the importance of the acetate group for its generation.

Understanding the potential carcinogenic potency of nitrosamines is necessary to setting acceptable intake limits. Nitrosamines and the components that can form them are commonly present in food, water, cosmetics, and tobacco. The recent observation of nitrosamines in pharmaceuticals highlighted the need for effective methods to determine acceptable intake limits. Herein, we describe two computational models that utilize properties based upon quantum mechanical calculations in conjunction with mechanistic insights and established data to determine the carcinogenic potency of a variety of common nitrosamines. These models can be applied to experimentally untested nitrosamines to aid in the establishment of acceptable intake limits.

Skin sensitization is a critical end point in occupational toxicology that necessitates the use of fast, accurate, and affordable models to aid in establishing handling guidance for worker protection. While many in silico models have been developed, the scarcity of reliable data for active pharmaceutical ingredients (APIs) and their intermediates (together regarded as pharmaceutical compounds) brings into question the reliability of these tools, which are largely constructed using publicly available nonspecialty chemicals. Here, we present the quantum-mechanical (QM) Computer-Aided Discovery and REdesign (CADRE) model, which was developed with the bioactive and structurally complex chemical space in mind by relying on the fundamentals of chemical interactions in key events (versus structural attributes of training-set data). Validated in this study on 345 APIs and intermediates, CADRE achieved 95% accuracy, sensitivity, and specificity and a combined 79% accuracy in assigning potency categories compared to the mouse local lymph node assay data. We show how historical outcomes from CADRE testing in the pharmaceutical space, generated over the past 10 years on ca. 2500 chemicals, can be used to probe the relationships between sensitization mechanisms (or the underlying chemical classes) and the probability of eliciting a sensitization response in mice of a given potency. We believe this information to be of value to both practitioners, who can use it to quickly screen and triage their data sets, as well as to model developers to fine-tune their structure-based tools. Lastly, we leverage our experimentally validated subset of APIs and intermediates to show the importance of dermal permeability on the sensitization potential and potency. We demonstrate that common physicochemical properties used to assess permeation, such as the octanol–water partition coefficient and molecular weight, are poor proxies for the more accurate energy-pair distributions that can be computed from mixed QM and classical simulations using model representations of the stratum corneum.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects. 4-Hydroxy-2-nonenal (HNE) levels are elevated in the spinal cord motor neurons of ALS patients, and HNE-modified proteins have been identified in the spinal cord tissue of an ALS transgenic mice model, suggesting that reactive aldehydes can contribute to motor neuron degeneration in ALS. One biological pathway of aldehyde detoxification involves conjugation with glutathione (GSH) or carnosine (Car). Here, the detection and quantification of Car, GSH, GSSG (glutathione disulfide), and the corresponding adducts with HNE, Car-HNE, and GS-HNE, were performed in muscle and liver tissues of a hSOD1^G93A ALS rat model by reverse-phase high-performance liquid chromatography coupled to electrospray ion trap tandem mass spectrometry in the selected reaction monitoring mode. A significant increase in the levels of GS-HNE and Car-HNE was observed in the muscle tissue of the end-stage ALS animals. Therefore, analyzing variations in the levels of these adducts in ALS animal tissue is crucial from a toxicological perspective and can contribute to the development of new therapeutic strategies.

Aerobic glycolysis is a metabolic reprogramming of tumor cells that is essential for sustaining their phenotype of fast multiplication by continuously supplying energy and mass. Pyruvate kinase M2 (PKM2) has a vital role in this process, which has given it high interest as a target for anticancer drug development. With potent toxicity to many types of cancer cells, polyphyllin II (PP2), a steroidal saponin isolated from the herbaceous plant Rhizoma paridis, brought to our attention that it might interfere with the PKM2 activity. In this study, we discovered that PP2 was a novel agonist of PKM2. PP2 activated recombinant PKM2 and changed the protein’s oligomeric state to activate intracellular PKM2. At the same time, PP2 suppressed its protein kinase function by decreasing the content of nuclear PKM2. The mRNA levels of its downstream genes, such as Glut1, LDHA, and MYC, were inhibited. In addition, PP2 induced oxidative stress by downregulating the expression and activity of antioxidant proteins such as NQO1, TrxR, and Trx in HT-1080 cells, which in turn led to mitochondrial dysfunction and ultimately induced apoptosis. Moreover, PP2 reduced the proliferation and migration of HT-1080 cells. Thus, targeting the glycolysis pathway offers an unprecedented mode of action for comprehending PP2’s pharmacological impacts and advances PP2’s further development in fibrosarcoma therapy.