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Chemical Research in Toxicology

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https://www.readbyqxmd.com/read/28426193/the-glutathione-conundrum-stoichiometric-disconnect-between-its-formation-and-oxidative-stress
#1
Gunnar Boysen
Glutathione (GSH) is the most abundant antioxidant and is believed to maintain redox potential in tissues, cells, and individual compartments. However, GSH concentrations in some tumor cells and tissues have been reported to be as high as 1-10 mM, a concentration that is up to 10,000-fold higher than that of reactive oxygen species. Critical quantitative evaluation of glutathione's proposed functions suggests that glutathione is an amino acid checkpoint. In this role, glutathione contributes to regulating cell proliferation and apoptosis, pending amino acid availability...
April 26, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28414904/in-silico-prediction-of-chemicals-binding-to-aromatase-with-machine-learning-methods
#2
Hanwen Du, Yingchun Cai, Hongbin Yang, Hongxiao Zhang, Yuhan Xue, Guixia Liu, Yun Tang, Weihua Li
Environmental chemicals may affect endocrine systems through multiple mechanisms, one of which is via effects on aromatase (also known as CYP19A1), an enzyme critical for maintaining the normal balance of estrogens and androgens in the body. Therefore, rapid and efficient identification of aromatase-related endocrine disrupting chemicals (EDCs) is important for toxicology and environment risk assessment. In this study, on the basis of the Tox21 10K compound library, in silico classification models for predicting aromatase binders/nonbinders were constructed by machine learning methods...
April 26, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28398727/use-of-the-distribution-coefficient-in-brain-polar-lipids-for-the-assessment-of-drug-induced-phospholipidosis-risk
#3
M Ceccarelli, B Wagner, R Alvarez-Sánchez, G Cruciani, L Goracci
In vitro safety assessment in early drug discovery represents an important step to detect potential safety-related liabilities. It reduces late stage attrition and allows candidate optimization. In this study, we report on the use of the LogDBPL assay (a recently published assay for the determination of drug distribution coefficients between an aqueous phase and porcine brain polar lipids extract) for phospholipidosis (PLD) risk evaluation. The LogDBPL parameter was first compared to the effective permeability in the parallel artificial membrane permeability assay (PAMPA), previously reported as correlating with PLD risk...
April 25, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28437613/evaluating-the-role-of-multidrug-resistance-protein-3-mdr3-inhibition-in-predicting-drug-induced-liver-injury-using-125-pharmaceuticals
#4
Michael D Aleo, Falgun Shah, Kan He, Paul D Bonin, A David Rodrigues
The role of bile salt export protein (BSEP) inhibition in drug-induced liver injury (DILI) has been investigated widely, while inhibition of the canalicular multidrug resistant protein 3 (MDR3) has received less attention. This transporter plays a pivotal role in secretion of phospholipids into bile and functions coordinately with BSEP to mediate the formation of bile acid-containing biliary micelles. Therefore, inhibition of MDR3 in human hepatocytes was examined across 125 drugs (70 of Most- and 55 of No-DILI-concern)...
April 24, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28316234/modeling-exposure-in-the-tox21-in-vitro-bioassays
#5
Fabian C Fischer, Luise Henneberger, Maria König, Kai Bittermann, Lukas Linden, Kai-Uwe Goss, Beate I Escher
High-throughput in vitro bioassays are becoming increasingly important in the risk characterization of anthropogenic chemicals. Large databases gather nominal effect concentrations (Cnom) for diverse modes of action. However, the biologically effective concentration can substantially deviate due to differences in chemical partitioning. In this study, we modeled freely dissolved (Cfree), cellular (Ccell), and membrane concentrations (Cmem) in the Tox21 GeneBLAzer bioassays for a set of neutral and ionogenic organic chemicals covering a large physicochemical space...
April 24, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28402640/mutagenic-replication-of-n-2-deoxyguanosine-benzo-a-pyrene-adducts-by-escherichia-coli-dna-polymerase-i-and-sulfolobus-solfataricus-dna-polymerase-iv
#6
A S Prakasha Gowda, Jacek Krzeminski, Shantu Amin, Zucai Suo, Thomas E Spratt
Benzo[a]pyrene, a potent human carcinogen, is metabolized in vivo to a diol epoxide that reacts with the N(2)-position of guanine to produce N(2)-BP-dG adducts. These adducts are mutagenic causing G to T transversions. These adducts block replicative polymerases but can be bypassed by the Y-family translesion synthesis polymerases. The mechanisms by which mutagenic bypass occurs is not well-known. We have evaluated base pairing structures using atomic substitution of the dNTP with two stereoisomers, 2'-deoxy-N-[(7R,8S,9R,10S)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine and 2'-deoxy-N-[(7S,8R,9S,10R)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine...
April 19, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28418643/diphenyl-diselenide-protects-against-methylmercury-induced-toxicity-in-saccharomyces-cerevisiae-via-the-yap1-transcription-factor
#7
Fabricio Luís Lovato, João B T Rocha, Cristiane Lenz Dalla Corte
Methylmercury (MeHg) is a ubiquitous and persistent environmental pollutant that induces serious neurotoxic effects. Diphenyl diselenide [(PhSe)2], an organoseleno-compound, exerts protective effects against MeHg toxicity, although the complete mechanism remains unclear. The aim of this study was to investigate the mechanisms involved in the protective effect of (PhSe)2 on the toxicity induced by MeHg using wild-type Saccharomyces cerevisiae and mutants with defects in enzymes and proteins of the antioxidant defense system (yap1Δ, ybp1Δ, ctt1Δ, cat1Δ, sod1Δ, sod2Δ, gsh1Δ, gsh2Δ, gtt1Δ, gtt2Δ, gtt3Δ, gpx1Δ, gpx2Δ, trx1Δ, trx2Δ, trx3Δ and trr2Δ)...
April 18, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28394575/1-3-butadiene-induced-adenine-dna-adducts-are-genotoxic-but-only-weakly-mutagenic-when-replicated-in-escherichia-coli-of-various-repair-and-replication-backgrounds
#8
Shiou-Chi Chang, Uthpala I Seneviratne, Jie Wu, Natalia Tretyakova, John M Essigmann
The adverse effects of the human carcinogen 1,3-butadiene (BD) are believed to be mediated by its DNA-reactive metabolites such as 3,4-epoxybut-1-ene (EB) and 1,2,3,4-diepoxybutane (DEB). The specific DNA adducts responsible for toxic and mutagenic effects of BD, however, have yet to be identified. Recent in vitro polymerase bypass studies of BD-induced adenine (BD-dA) adducts show that DEB-induced N(6),N(6)-DHB-dA (DHB = 2,3-dihydroxybutan-1,4-diyl) and 1,N(6)-γ-HMHP-dA (HMHP = 2-hydroxy-3-hydroxymethylpropan-1,3-diyl) adducts block replicative DNA polymerases but are bypassed by human polymerases η and κ, leading to point mutations and deletions...
April 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28395138/formation-of-s-2-n-6-deoxyadenosinyl-ethyl-glutathione-in-dna-and-replication-past-the-adduct-by-translesion-dna-polymerases
#9
Carl A Sedgeman, Yan Su, F Peter Guengerich
1,2-Dibromoethane (DBE, ethylene dibromide) is a potent carcinogen due at least in part to its DNA cross-linking effects. DBE cross-links glutathione (GSH) to DNA, notably to sites on 2'-deoxyadenosine and 2'-deoxyguanosine ( Cmarik , J. L. , et al. ( 1991 ) J. Biol. Chem. 267 , 6672 - 6679 ). Adduction at the N6 position of 2'-deoxyadenosine (dA) had not been detected, but this is a site for the linkage of O(6)-alkylguanine DNA alkyltransferase ( Chowdhury , G. , et al. ( 2013 ) Angew. Chem. Int. Ed. 52 , 12879 - 12882 )...
April 14, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28388097/replicative-bypass-studies-of-%C3%AE-anomeric-lesions-of-2-deoxyribonucleosides-in-vitro
#10
Nicole L Williams, Nicholas J Amato, Yinsheng Wang
Genomic integrity is constantly challenged by a variety of endogenous and exogenous DNA damaging agents, which can lead to the formation of 10(4)-10(5) DNA lesions per cell per day. Reactive oxygen species (ROS) represent a major type of DNA damaging agent. Specifically, a hydroxyl radical can attack the C1' position of 2-deoxyribose, and the ensuing carbon-centered radical, if improperly repaired, can cause the inversion of stereochemical configuration at the C1' to give α-anomeric lesions. In this study, we assessed the replicative bypass of α-dA, α-dT, α-dC, and α-dG in template DNA by conducting primer extension assays with the use of purified translesion synthesis DNA polymerases...
April 14, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28402675/mechanistic-insight-into-the-molecular-tio2-mediated-gas-phase-detoxication-of-dmmp-a-theoretical-approach
#11
Tamalika Ash, Tanay Debnath, Avik Ghosh, Abhijit Kr Das
The detoxication of DMMP (Dimethyl methylphosphonate) mediated by molecular TiO2 has been investigated computationally using density functional theory (DFT). From our previous studies, it is evident that the unimolecular detoxication of OPCs (Organophosphorus compound) is kinetically unfeasible at room temperature due to significantly high activation barrier. Thus, the aim of our work is to find out whether molecular TiO2 can make any significant impact on the kinetic feasibility of the detoxication processes or not...
April 12, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28398741/adductomic-screening-of-hemoglobin-adducts-and-monitoring-of-micronuclei-in-school-age-children
#12
Henrik Carlsson, Jenny Aasa, Natalia Kotova, Daniel Vare, Pedro F M Sousa, Per Mikael Rydberg, Lilianne Abramsson-Zetterberg, Margareta Åsa Törnqvist
Electrophilic compounds/metabolites present in humans, originating from endogenous processes or exogenous exposure, pose a risk for health effects through their reactions with nucleophilic sites in proteins and DNA, forming adducts. Adductomic approaches are developed to screen for adducts to biomacromolecules in vivo by mass spectrometry (MS), with the aim to detect adducts corresponding to unknown exposures from electrophiles. In the present study, adductomic screening was performed using blood samples from healthy children about 12 years old (n=51)...
April 11, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28334528/why-prodrugs-and-propesticides-succeed
#13
John E Casida
What are the advantages of bioactivation in optimizing drugs and pesticides? Why are there so many prodrugs and propesticides? These questions are examined here by considering compounds selected on the basis of economic value or market success in 2015. The 100 major drugs and 90 major pesticides are divided into ones acting directly and those definitely or possibly requiring bioactivation. Established or candidate prodrugs accounted for 19% of the total drug sales, with corresponding values of 20, 37, and 17% for proinsecticides, proherbicides, and profungicides...
April 7, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28380295/non-catalytic-n-terminal-domains-of-dna-polymerase-lambda-affect-its-cellular-localization-and-dna-damage-response
#14
Anthony Aaron Stephenson, David James Taggart, Zucai Suo
Specialized DNA polymerases, such as DNA polymerase lambda (Polλ), are important players in DNA damage tolerance and repair pathways. Knowing how DNA polymerases are regulated and recruited to sites of DNA damage is imperative to understanding these pathways. Recent work has suggested that Polλ plays a role in several distinct DNA damage tolerance and repair pathways. In this paper, we report previously unknown roles of the N-terminal domains of human Polλ for modulating its involvement in DNA damage tolerance and repair...
April 5, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28222263/reaction-mechanism-of-covalent-modification-of-phosphatidylethanolamine-lipids-by-reactive-aldehydes-4-hydroxy-2-nonenal-and-4-oxo-2-nonenal
#15
Katarina Vazdar, Danijela Vojta, Davor Margetić, Mario Vazdar
4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) are biologically important reactive aldehydes formed during oxidative stress in phospholipid bilayers. They are highly reactive species due to presence of several reaction centers and can react with amino acids in peptides and proteins, as well as phosphoethanolamine (PE) lipids, thus modifying their biological activity. The aim of this work is to study in a molecular detail the reactivity of HNE and ONE toward PE lipids in a simplified system containing only lipids and reactive aldehydes in dichloromethane as an inert solvent...
March 6, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28219012/tyrosinase-catalyzed-oxidation-of-the-leukoderma-inducing-agent-raspberry-ketone-produces-e-4-3-oxo-1-butenyl-1-2-benzoquinone-implications-for-melanocyte-toxicity
#16
Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa Wakamatsu
The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-quinones...
March 6, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28161940/copper-2-hypothesis-for-causation-of-the-current-alzheimer-s-disease-epidemic-together-with-dietary-changes-that-enhance-the-epidemic
#17
George J Brewer
Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveal the epidemic is a creature of the last century. That is, the disease was also rare in developed countries, until the 20th century. It is disappointing that these historical and demographic facts have been ignored by the Alzheimer's disease scientific community...
March 3, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28248093/characterizing-sirtuin-3-deacetylase-affinity-for-aldehyde-dehydrogenase-2
#18
Peter S Harris, Joe D Gomez, Donald S Backos, Kristofer S Fritz
Mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in the detoxification of reactive aldehydes generated through endogenous and exogenous sources. The biochemical regulation of enzyme activity through post-translational modification provides an intricate response system regulating mitochondrial detoxification pathways. ALDH2 is a known target of lysine acetylation, which arises as a consequence of mitochondrial bioenergetic flux and sirtuin deacetylase activity. The mitochondrial deacetylase Sirtuin 3 (SIRT3) has been reported to alter ALDH2 lysine acetylation status, yet the mechanism and consequence of this interaction remain unknown...
March 1, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28147486/validation-of-a-multiparametric-high-content-screening-assay-for-predictive-investigative-cytotoxicity-evidence-from-technology-transfer-studies-and-literature-review
#19
Peter James O'Brien, Anna Edvardsson
A multiparametric, live-cell, high-content-screening (HCS) cytotoxicity assay was first demonstrated in 2006 ( Arch. Toxicol. 2006 , 80 , 580 - 604 ) to be highly concordant with human hepatotoxicity, including idiosyncratic hepatotoxicities and other target organ toxicities in contrast to historical assays. The success of the assay was attributed to its simultaneous measurement of multiple appropriate "cytobiomarkers": use of human cells with xenometabolic competence for toxicities mediated by metabolites, 72 h exposure to enable expression of slower-acting toxicants, exposure to a wide-range of concentrations from 30- to 100-fold the efficacious concentration, and normalizing the in vitro cytotoxic concentration to an estimate of the in vivo concentration of exposure...
February 22, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28165728/hepatoprotective-effect-of-%C3%AF-glutathione-in-a-murine-model-of-acetaminophen-induced-liver-toxicity
#20
Swati S More, Jaime Nugent, Ashish P Vartak, Steffan M Nye, Robert Vince
Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios...
February 16, 2017: Chemical Research in Toxicology
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