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Chemical Research in Toxicology

Reema Goel, Zachary Bitzer, Samantha M Reilly, Neil Trushin, Jonathan Foulds, Joshua Muscat, Jason Liao, Ryan J Elias, John P Richie
Free radicals in tobacco smoke are thought to be an important cause of smoking-induced diseases, yet the variation in free radical exposure to smokers from different brands of commercially available cigarettes is unknown. We measured the levels of highly reactive gas-phase and stable particulate-phase radicals in mainstream cigarette smoke by electron paramagnetic resonance (EPR) spectroscopy with and without the spin-trapping agent phenyl-N-tert-butylnitrone (PBN), respectively, in 27 popular US cigarettes and the 3R4F research cigarette, machine-smoked according to the FTC protocol...
March 20, 2017: Chemical Research in Toxicology
Rance Nault, Kelly A Fader, Todd A Lydic, Timothy R Zacharewski
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic steatosis mediated by the aryl hydrocarbon receptor. To further characterize TCDD-elicited hepatic lipid accumulation, mice were gavaged with TCDD every 4 days for 28 days. Liver samples were examined using untargeted lipidomics with structural confirmation of lipid species by targeted high-resolution MS/MS, and data were integrated with complementary RNA-Seq analyses. Approximately 936 unique spectral features were detected, of which 379 were confirmed as unique lipid species...
March 20, 2017: Chemical Research in Toxicology
Fabian Christoph 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...
March 19, 2017: Chemical Research in Toxicology
Dan Carmany, Andrew J Walz, Fu-Lian Hsu, Bernard Benton, David Burnett, Jennifer Gibbons, Daan Noort, Trevor Glaros, Jennifer W Sekowski
Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways. While much is known about the primary toxicity mechanisms of nerve agents, there remains a paucity of information regarding impacts on other pathways and systemic effects...
March 16, 2017: Chemical Research in Toxicology
Bei Gao, Liang Chi, Ridwan Mahbub, Xiaoming Bian, Pengcheng Tu, Hongyu Ru, Kun Lu
Lead exposure remains a global public health issue, and the recent Flint water crisis has renewed public concern about lead toxicity. The toxicity of lead has been well established in a variety of systems and organs. The gut microbiome has been shown to be highly involved in many critical physiological processes, including food digestion, immune system development, and metabolic homeostasis. However, despite the key role of the gut microbiome in human health, the functional impact of lead exposure on the gut microbiome has not been studied...
March 16, 2017: Chemical Research in Toxicology
Na Le Dang, Tyler B Hughes, Grover P Miller, S Joshua Swamidass
Structural alerts are commonly used in drug discovery to identify molecules likely to form reactive metabolites and thereby become toxic. Unfortunately, as useful as structural alerts are, they do not effectively model if, when, and why metabolism renders safe molecules toxic. Toxicity due to a specific structural alert is highly conditional, depending on the metabolism of the alert, the reactivity of its metabolites, dosage, and competing detoxification pathways. A systems approach, which explicitly models these pathways, could more effectively assess the toxicity risk of drug candidates...
March 14, 2017: Chemical Research in Toxicology
Angela Kaempfer, Rita La Spina, Douglas Gilliland, Sandro Valzacchi, David Asturiol, Vicki Stone, Agnieszka Kinsner-Ovaskainen
Silver (Ag) is the most common nanomaterial (NM) in consumer products. Much research has been focused on elucidating the potential impact of Ag-containing NMs on human health, e.g. cytotoxicity, genotoxicity or pro-inflammatory responses. In the case of pro-inflammatory response a frequently used endpoint is the induction of nitric oxide (NO), which is indirectly quantified as nitrite (NO2-) with the Griess reaction. After preliminary studies in a macrophage-like cell culture system showed anomalous false negative results in presence of silver nanoparticles (Ag NPs), we studied the influence of Ag on the detection of NO2- in a cell-free environment...
March 10, 2017: Chemical Research in Toxicology
Xun Ming, Erin D Michaelson-Richie, Arnold Groehler, Peter W Villalta, Colin Campbell, Natalia Y Tretyakova
Platinum-based antitumor drugs such as 1,1,2,2-cis-diamminedichloroplatinum(II) (cisplatin), carboplatin, and oxaliplatin are currently used to treat nearly 50% of all cancer cases, and novel platinum based agents are under development. The antitumor effects of cisplatin and other platinum compounds are attributed to their ability to induce interstrand DNA-DNA cross-links, which are thought to inhibit tumor cell growth by blocking DNA replication and/or preventing transcription. However, platinum agents also induce significant numbers of unusually bulky and helix-distorting DNA-protein cross-links (DPCs), which are poorly characterized because of their unusual complexity...
March 10, 2017: Chemical Research in Toxicology
Meng Huang, Clementina A Mesaros, Linda C Hackfield, Richard P Hodge, Tianzhu Zang, Ian Alexander Blair, Trevor M Penning
Exposure to petrogenic polycyclic aromatic hydrocarbons (PPAHs) in the food-chain is the major human health hazard associated with the Deepwater Horizon oil spill. C4-Phenanthrenes are representative PPAHs present in the crude oil and could contaminate the seafood. We describe the metabolism of a C4-phenanthrene regioisomer retene (1-methyl-7-isopropyl-phenanthrene) in human HepG2 cells as a model for metabolism in human hepatocytes. Retene because of its sites of alkylation cannot be metabolized to a diol-epoxide...
March 9, 2017: Chemical Research in Toxicology
Jie Zhao, Jinming Wu, Zhen Yang, Hailing Li, Zhonghong Gao
Amyloid-β plaques and oxidative stress are the major hallmarks of Alzheimer's disease. Our previous study found that: heme-Aβ complex enhanced the catalytic effect of free heme on protein tyrosine nitration in the presence of hydrogen peroxide (H2O2), nitrite (NO2-). Y10 in Aβ could be the first target to be nitrated. We also found that nitration of Aβ1-40 significantly decreased its aggregation. However, a contrary report showed that nitration of Aβ1-42 by peroxynitrite enhanced its aggregation. To rule out the interference of peroxynitrite caused Aβ oxidation, we used synthetic Y10 nitrated Aβ1-42 to study the influence of Y10 nitration on Aβ1-42's aggregation and cytotoxicity in this study...
March 8, 2017: Chemical Research in Toxicology
Fangyi Chen, Ke Bian, Qi Tang, Bogdan I Fedeles, Vipender Singh, Zachary T Humulock, John M Essigmann, Deyu Li
Cancer-associated mutations often lead to perturbed cellular energy metabolism and accumulation of potentially harmful oncometabolites. One example is the chiral molecule 2-hydroxyglutarate (2HG); its two stereoisomers (D- and L-2HG) have been found with abnormally high concentrations in tumors featuring anomalous metabolic pathways. 2HG has been demonstrated to competitively inhibit several α-ketoglutarate (αKG)- and non-heme iron-dependent dioxygenases, including some of the AlkB family DNA repair enzymes, such as ALKBH2 and ALKBH3...
March 7, 2017: Chemical Research in Toxicology
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
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
Rosa Chan, Leslie Z Benet
Drug-induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals. DILI has been shown to be dependent on both daily dose and extent of hepatic metabolism. Yet, early in drug development daily dose is unknown. Here, we perform a comprehensive analysis of the published hypotheses that attempt to predict DILI, including a new analysis of the Biopharmaceutics Drug Disposition Classification System (BDDCS) in evaluating the severity of DILI warning in drug labels approved by the FDA and the withdrawal status due to ADRs...
March 3, 2017: Chemical Research in Toxicology
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
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
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
Alessia Stornetta, Peter W Villalta, Frederike Gossner, William R Wilson, Silvia Balbo, Shana J Sturla
PR104A is an experimental DNA-alkylating hypoxia-activated prodrug that can also be activated in an oxygen-independent manner by the two-electron aldo-keto reductase 1C3. Nitroreduction leads to the formation of cytotoxic hydroxylamine (PR104H) and amine (PR104M) metabolites, which induce DNA mono and cross-linked adducts in cells. PR104A-derived DNA adducts can be utilized as drug-specific biomarkers of efficacy and as a mechanistic tool to elucidate the cellular and molecular effects of PR104A. Toward this goal, a mass spectrometric bioanalysis approach based on a stable isotope-labeled adduct mixture (SILAM) and selected reaction monitoring (SRM) data acquisition for relative quantitation of PR104A-derived DNA adducts in cells was developed...
February 19, 2017: Chemical Research in Toxicology
Lina Gao, Esra Mutlu, Leonard B Collins, Nigel J Walker, Hadley J Hartwell, James R Olson, Wei Sun, Avram Gold, Louise M Ball, James A Swenberg
DNA oxidation damage has been regarded as one of the possible mechanisms for the hepatic carcinogenesis of dioxin-like compounds (DLCs). In this study, we evaluated the toxic equivalency factor (TEF) from the standpoint of induced DNA oxidation products and their relationship to toxicity and carcinogenicity. Nine DNA oxidation products were analyzed in the liver of female Sprague-Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alone or the tertiary mixture of TCDD, 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) by gavage for 14, 31, and 53 weeks (5 days/week) by LC-MS/MS: 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo); 1,N(6)-etheno-2'-deoxyadenosine (1,N(6)-εdAdo); N(2),3-ethenoguanine (N(2),3-εG); 7-(2-oxoethly)guanine (7-OEG); 1,N(2)-etheno-2'-deoxyguanosine (1,N(2)-εdGuo); malondialdehyde (M1dGuo); acrolein (AcrdGuo); crotonaldehyde (CrdGuo); and 4-hydroxynonenal (HNEdGuo) derived 2'-deoxyguanosine adducts...
February 16, 2017: Chemical Research in Toxicology
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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