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Chemical Research in Toxicology

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https://www.readbyqxmd.com/read/28085253/crowd-sourced-verification-of-computational-methods-and-data-in-systems-toxicology-a-case-study-with-a-heat-not-burn-candidate-modified-risk-tobacco-product
#1
Carine Poussin, Vincenzo Belcastro, Florian Martin, Stéphanie Boué, Manuel C Peitsch, Julia Hoeng
Systems toxicology intends to quantify the effect of toxic molecules in biological systems and unravel their mechanisms of toxicity. The development of advanced computational methods is required for analyzing and integrating high throughput data generated for this purpose as well as for extrapolating predictive toxicological outcomes and risk estimates. To ensure performance and reliability of the methods and verify conclusions from systems toxicology data analysis, it is important to conduct unbiased evaluations by independent third parties...
January 13, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28080046/application-of-2-aminothiazoline-4-carboxylic-acid-as-a-forensic-marker-of-cyanide-exposure
#2
Monika Rużycka, Joanna Giebułtowicz, Marcin Fudalej, Paweł Krajewski, Piotr Wroczyński
Cyanides are infamous for their highly poisonous properties. Accidental cyanide poisoning occurs frequently, but occasionally, intentional poisonings also occur. Inhalation of fumes generated by fire may also cause cyanide poisoning. There are many limitations in direct analysis of cyanide. 2-Aminothiazoline-4-carboxylic acid (ATCA), a cyanide metabolite, seems to be the only surrogate that is being used in the detection of cyanide because of its stability and its cyanide-dependent quality in biological matrix...
January 12, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28029781/aryl-hydrocarbon-receptor-activation-contributes-to-benzanthrone-induced-hyperpigmentation-via-modulation-of-melanogenic-signaling-pathways
#3
Sabiya Abbas, Shamshad Alam, Krishna P Singh, Mahadeo Kumar, Shailendra K Gupta, Kausar M Ansari
Benzanthrone (BA), an oxidized polycyclic aromatic hydrocarbon (PAH), has been found to be a potential health threat to occupational workers involved in dye manufacturing factories. It has been observed that occupational workers become exposed to BA either during manufacturing, pulverization, or storage and developed various kinds of skin diseases like contact dermatitis, itching, erythema, roughness, and foremost, hyperpigmentation. It has been shown that some environmental organic pollutants (POPs) like dioxins, furans, and polychlorinated biphenyls (PCBs) may act as ligands for the aryl hydrocarbon receptor (AhR) and regulate hyperpigmentation...
January 12, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28076683/modulation-of-cytotoxicity-by-transcription-coupled-nucleotide-excision-repair-is-independent-of-the-requirement-for-bioactivation-of-acylfulvene
#4
Claudia Otto, Graciela Spivak, Claudia Marie Nathalie Aloisi, Mirco Menigatti, Hanspeter Nägeli, Philip C Hanawalt, Marina Tanasova, Shana J Sturla
Bioactivation as well as DNA repair affect the susceptibility of cancer cells to the action of DNA-alkylating chemotherapeutic drugs. However, information is limited with regard to the relative contributions of these processes to the biological outcome of metabolically activated DNA alkylating agents. We evaluated the influence of cellular bioactivation capacity and DNA repair on cytotoxicity of the DNA alkylating agent, acylfulvene (AF). We compared cytotoxicity and RNA synthesis inhibition by AF and its synthetic activated analog iso-M0 in a panel of fibroblast cell lines with deficiencies in transcription-coupled (TC-NER) or global genome nucleotide excision repair (GG-NER)...
January 11, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28068470/virtual-cross-linking-of-the-active-nemorubicin-metabolite-pnu-159682-to-double-stranded-dna
#5
Matteo Scalabrin, Luigi Quintieri, Manlio Palumbo, Federico Riccardi Sirtori, Barbara Gatto
The DNA alkylating mechanism of PNU-159682 (PNU), a highly potent metabolite of the anthracycline nemorubicin, was investigated by gel-electrophoretic, HPLC-UV and micro-HPLC/mass spectrometry (MS) measurements. PNU quickly reacted with double-stranded oligonucleotides, but not with single-stranded sequences, to form covalent adducts which were detectable by denaturing polyacrylamide gel electrophoresis (DPAGE). Ion-pair reverse-phase HPLC-UV analysis on CG rich duplex sequences having a 5'-CCCGGG-3' central core showed the formation of two types of adducts with PNU, which were stable and could be characterized by micro-HPLC/MS...
January 9, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28067485/honokiol-inhibits-dna-polymerases-%C3%AE-and-%C3%AE-and-increases-bleomycin-sensitivity-of-human-cancer-cells
#6
Prakasha Gowda, Zucai Suo, Thomas E Spratt
A major concept to sensitize cancer cells to DNA damaging agents is by inhibiting proteins in the DNA repair pathways. X-Family DNA polymerases play critical roles in both base excision repair (BER) and non-homologous end joining (NHEJ). In this study, we examined the effectiveness of honokiol to inhibit human DNA polymerase β (pol β), which is involved in BER, and DNA polymerase λ (pol λ), which is involved in NHEJ. Kinetic analysis with purified showed that honokiol inhibited DNA polymerase activity. The inhibition mode for the polymerases was a mixed-function noncompetitive inhibition with respect to the substrate, dCTP...
January 9, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28045533/computational-model-of-secondary-palate-fusion-and-disruption
#7
M Shane Hutson, Maxwell C K Leung, Nancy Baker, Richard M Spencer, Thomas B Knudsen
Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from chemical-induced cellular alterations, we built a multi-cellular agent-based model in CompuCell3D that recapitulates the cellular networks and collective cell behavior underlying growth and fusion of the mammalian secondary palate. The model incorporated multiple signaling pathways (TGFβ, BMP, FGF, EGF, SHH) in a biological framework to recapitulate morphogenetic events from palatal outgrowth through midline fusion...
January 3, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28045255/application-of-a-fragment-based-reactivity-profiler-for-the-prediction-of-human-health-and-environmental-toxicity-endpoints-skin-sensitisation-potency-and-aquatic-toxicity
#8
David Jonathan Ebbrell, Judith Clare Madden, Mark T D Cronin, Terry Wayne Schultz, Steven J Enoch
Toxicological effects, such as skin sensitisation and aquatic toxicity, can occur as a result of covalent bond formation between electrophilic chemicals and biological nucleophiles. One common mechanism through which covalent bonds may form is Michael addition. In silico profilers, consisting of structural alerts, have been developed that are able to identify the potential for a chemical to act as a Michael acceptor. However, such in silico profilers provide no information on rate of covalent bond formation (reactivity)...
January 3, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27978618/electrophilic-modification-of-pkm2-by-4-hydroxynonenal-and-4-oxononenal-results-in-protein-cross-linking-and-kinase-inhibition
#9
Jeannie M Camarillo, Jody C Ullery, Kristie L Rose, Lawrence J Marnett
Rapidly proliferating cells require an increased rate of metabolism to allow for the production of nucleic acids, amino acids, and lipids. Pyruvate kinase catalyzes the final step in the glycolysis pathway, and different isoforms display vastly different catalytic efficiencies. The M2 isoform of pyruvate kinase (PKM2) is strongly expressed in cancer cells and contributes to aerobic glycolysis in what is commonly termed the Warburg effect. Here, we show that PKM2 is covalently modified by the lipid electrophiles 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE)...
January 3, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27936622/dna-adducts-from-anticancer-drugs-as-candidate-predictive-markers-for-precision-medicine
#10
Alessia Stornetta, Maike Zimmermann, George D Cimino, Paul T Henderson, Shana J Sturla
Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed...
January 3, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28027439/carbamate-insecticides-target-human-melatonin-receptors
#11
Marina Popovska-Gorevski, Margarita L Dubocovich, Rajendram V Rajnarayanan
Carbaryl (1-naphthyl methylcarbamate) and carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate) are among the most toxic insecticides, implicated in a variety of diseases including diabetes and cancer among others. Using an integrated pharmacoinformatics based screening approach, we have identified these insecticides to be structural mimics of the neurohormone melatonin and were able to bind to the putative melatonin binding sites in MT1 and MT2 melatonin receptors in silico. Carbaryl and carbofuran then were tested for competition with 2-[125I]-iodomelatonin (300 pM) binding to hMT1 or hMT2 receptors stably expressed in CHO cells...
December 27, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27943678/cytotoxicity-of-tirapazamine-3-amino-1-2-4-benzotriazine-1-4-dioxide-induced-dna-damage-in-chicken-dt40-cells
#12
Takahito Moriwaki, Saki Okamoto, Hiroyuki Sasanuma, Hideko Nagasawa, Shunichi Takeda, Shin-Ichiro Masunaga, Keizo Tano
Tirapazamine (TPZ) is an anticancer drug with highly selective cytotoxicity toward hypoxic cells. TPZ is converted to a radical intermediate under hypoxic conditions, and this intermediate interacts with intracellular macromolecules, including DNA. TPZ has been reported to indirectly induce DNA double-strand breaks (DSBs) through the formation of various intermediate DNA lesions under hypoxic conditions. Although the topoisomerase II-DNA complex has been identified as one of these intermediates, other lesions have not yet been defined...
December 27, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28001416/tobacco-specific-nitrosamines-in-the-tobacco-and-mainstream-smoke-of-u-s-commercial-cigarettes
#13
Selvin H Edwards, Lana M Rossiter, Kenneth M Taylor, Matthew R Holman, Liqin Zhang, Yan S Ding, Clifford H Watson
Tobacco-specific nitrosamines (TSNAs) are N-nitroso-derivatives of pyridine-alkaloids (e.g., nicotine) present in tobacco and cigarette smoke. Two TSNAs, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are included on the Food and Drug Administration's list of harmful and potentially harmful constituents (HPHCs) in tobacco products and tobacco. The amounts of four TSNAs (NNK, NNN, N-nitrosoanabasine (NAB), and N'-nitrosoanatabine (NAT)) in the tobacco and mainstream smoke from 50 U...
December 21, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28001376/thirdhand-smoke-new-evidence-challenges-and-future-directions
#14
Peyton Jacob, Neal L Benowitz, Hugo Destaillats, Lara Gundel, Bo Hang, Manuela Martins-Green, Georg E Matt, Penelope J E Quintana, Jonathan M Samet, Suzaynn F Schick, Prue Talbot, Noel J Aquilina, Melbourne F Hovell, Jian-Hua Mao, Todd P Whitehead
Thirdhand smoke (THS) is the contamination that persists after secondhand tobacco smoke has been emitted into air. It refers to the tobacco-related gases and particles that become embedded in materials, such as the carpet, walls, furniture, blankets, and toys. THS is not strictly smoke, but chemicals that adhere to surfaces from which they can be released back into the air, undergo chemical transformations and/or accumulate. Currently, the hazards of THS are not as well documented as the hazards of secondhand smoke (SHS)...
December 21, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28001369/stem-cell-transcriptome-responses-and-corresponding-biomarkers-that-indicate-the-transition-from-adaptive-responses-to-cytotoxicity
#15
Tanja Waldmann, Marianna Grinberg, André König, Eugen Rempel, Stefan Schildknecht, Margit Henry, Anna-Katharina Holzer, Nadine Dreser, Vaibhav Shinde, Agapios Sachinidis, Jörg Rahnenführer, Jan G Hengstler, Marcel Leist
Analysis of transcriptome changes has become an established method to characterize the reaction of cells to toxicants. Such experiments are mostly performed at compound concentrations close to the cytotoxicity threshold. At present, little information is available on concentration-dependent features of transcriptome changes, in particular, at the transition from noncytotoxic concentrations to conditions that are associated with cell death. Thus, it is unclear in how far cell death confounds the results of transcriptome studies...
December 21, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27951635/mutagenicity-of-a-model-dna-peptide-cross-link-in-human-cells-roles-of-translesion-synthesis-dna-polymerases
#16
Paritosh Pande, Shaofei Ji, Shivam Mukherjee, Orlando D Schärer, Natalia Y Tretyakova, Ashis K Basu
DNA-protein cross-links are formed upon exposure of cellular DNA to various agents, including antitumor drugs, UV light, transition metals, and reactive oxygen species. They are thought to contribute to cancer, aging, and neurodegenerative diseases. It has been proposed that DNA-protein cross-links formed in cells are subject to proteolytic degradation to the corresponding DNA-peptide cross-links (DpCs). To investigate the effects of DpCs on DNA replication, we have constructed plasmid DNA containing a 10-mer Myc peptide covalently linked to C7 of 7-deaza-dG, a hydrolytically stable mimic of N7-dG lesions...
December 21, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27997139/isotope-dilution-nanolc-esi-hrms-3-quantitation-of-urinary-n7-1-hydroxy-3-buten-2-yl-guanine-adducts-in-humans-and-their-use-as-biomarkers-of-exposure-to-1-3-butadiene
#17
Dewakar Sangaraju, Emily J Boldry, Yesha M Patel, Vernon Walker, Irina Stepanov, Daniel O Stram, Dorothy K Hatsukami, Natalia Y Tretyakova
1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a known human carcinogen. Occupational exposure to BD in the polymer and monomer industries is associated with an increased incidence of lymphoma. BD is present in automobile exhaust, cigarette smoke, and forest fires, raising concern about potential exposure of general population to this carcinogen. Following inhalation exposure, BD is bioactivated to 3,4-epoxy-1-butene (EB). If not detoxified, EB is capable of modifying guanine and adenine bases of DNA to form nucleobase adducts, which interfere with accurate DNA replication and cause cancer-initiating mutations...
December 20, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27930886/histone-adduction-and-its-functional-impact-on-epigenetics
#18
James J Galligan, Lawrence J Marnett
Bioactive electrophiles generated from the oxidation of endogenous and exogenous compounds are a contributing factor in numerous disease states. Their toxicity is largely attributed to the covalent modification of cellular nucleophiles, including protein and DNA. With regard to protein modification, the side-chains of Cys, His, Lys, and Arg residues are critical targets. This results in the generation of undesired protein post-translational modifications (PTMs) that can trigger dire cellular consequences. Notably, histones are Lys- and Arg-rich proteins, providing a fertile source for adduction by both exogenous and endogenous electrophiles...
December 20, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27992190/unveiling-the-variability-of-quartz-hazard-in-light-of-recent-toxicological-findings
#19
Cristina Pavan, Bice Fubini
The variability of quartz hazard stands as one of the most puzzling issues in particle toxicology, notwithstanding the fact that silicosis, the most ancient occupational disease, was the very topic from which the study of the toxicity of particulates developed. Over the years, other adverse effects of silica particles (i.e., lung cancer and autoimmune diseases) were detected and described. However, a few gaps are still present in the physicochemical determinants and cellular pathways involved in the mechanisms of silica pathogenicity...
December 19, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27989119/biomonitoring-human-albumin-adducts-the-past-the-present-and-the-future
#20
Gabriele Sabbioni, Robert J Turesky
Serum albumin (Alb) is the most abundant protein in blood plasma. Alb reacts with many carcinogens and/or their electrophilic metabolites. Studies conducted over 20 years ago showed that Alb forms adducts with the human carcinogens aflatoxin B1 and benzene, which were successfully used as biomarkers in molecular epidemiology studies designed to address the role of these chemicals in cancer risk. Alb forms adducts with many therapeutic drugs or their reactive metabolites such as β-lactam antibiotics, acetylsalicylic acid, acetaminophen, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents, and antiretroviral therapy drugs...
December 18, 2016: Chemical Research in Toxicology
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