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Chemical Research in Toxicology

Stephen S Hecht
No abstract text is available yet for this article.
December 28, 2017: Chemical Research in Toxicology
Guang Yang, Yuko Ibuki
Aldehydes are widespread environmental and industrial compounds to which humans are frequently exposed. Despite their significant health risk, the mechanisms underlying aldehyde toxicity are poorly understand. We recently demonstrated that cigarette sidestream smoke (CSS) inhibited nucleotide excision repair (NER), and this was attributed to aldehydes in CSS. In the present study, we examined the influence of saturated and unsaturated aldehydes on NER. The human keratinocyte cell line, HaCaT was treated with aldehydes and then exposed to UVB...
December 28, 2017: Chemical Research in Toxicology
Shalenie P den Braver-Sewradj, Michiel W den Braver, Robin M Toorneman, Stephanie van Leeuwen, Yongjie Zhang, Stefan J Dekker, Nico P E Vermeulen, Jan N M Commandeur, J Chris Vos
Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM...
December 27, 2017: Chemical Research in Toxicology
Douglas Edward Stack, John Albert Conrad, Bejan Mahmud
Bisphenol A (BPA) has received considerable attention as an endocrine disrupting chemical and a possible substrate for genotoxic metabolites. BPA metabolism leads to formation of electrophilic o-quinones cable of binding to DNA and other endogenous nucleophiles. We have structurally identified the products resulting from the reaction of bisphenol A-3,4-quinone (BPAQ) with N-acetylcysteine (NAC) and glutathione (GSH). The major and minor isomers are both the result of 1,6-conjugate addition and are produced almost instantly in high yield...
December 27, 2017: Chemical Research in Toxicology
Martin Gladović, Eva Španinger, Urban Bren
Acrylonitrile (AN) is widely used in the manufacture of resins, plastics and polymers, where workers are exposed to it during its production, transportation and application. After intake a portion of AN is converted to cyanoethylene oxide (CEO) by cytochrome P450 2E1. Both AN and CEO represent possible chemical carcinogens leading to DNA damage mainly in the form of the major 7-(2-oxoethyl)deoxyguanosine adduct. A kinetic model for its formation was devised and a corresponding second-order rate constant obtained from the experimental data on the reaction with CEO...
December 22, 2017: Chemical Research in Toxicology
James T Wilson, Cole A Fief, Klarissa Jackson, Susan L Mercer, Joseph E Deweese
Topoisomerase II is a critical enzyme in replication, transcription, and the regulation of chromatin topology. Several anticancer agents target topoisomerases in order to disrupt cell growth. Cannabidiol is a major non-euphoriant, pharmacologically active component of cannabis. Previously, we examined the cannabidiol derivative HU-331 in order to characterize the mechanism of the compound against topoisomerase IIα. In this current work, we explore whether cannabidiol (CBD) impacts topoisomerase II activity, and we additionally examine the activity of these compounds against topoisomerase IIβ...
December 22, 2017: Chemical Research in Toxicology
Manuela Murko, Brittany Elek, Miroslav Styblo, David James Thomas, Kevin A Francesconi
In humans, early life exposure to inorganic arsenic is associated with adverse health effects. Inorganic arsenic in utero or in early postnatal life also produces adverse health effects in offspring of pregnant mice that consumed drinking water containing low part per billion levels of inorganic arsenic. Because aggregate exposure of pregnant mice to inorganic arsenic from both drinking water and food has not been fully evaluated in experimental studies, quantifying arsenic exposure of the developing mouse is problematic...
December 15, 2017: Chemical Research in Toxicology
Wenji Li, Zheng-Yuan Su, Yue Guo, Chengyue Zhang, RenYi Wu, Linbo Gao, Xi Zheng, Zhi-Yun Du, Kun Zhang, Ah-Ng Kong
The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes. We aimed to investigate the effects of (3E,5E)-3,5-Bis(3,4,5-trimethoxybenzylidene) -tetrahydrothiopyran-4-one (F10) and (3E,5E)-3,5-Bis(3,4,5-trimethoxybenzylidene) -tetrahydropyran-4-one (E10), two synthetic curcumin derivatives, on restoring Nrf2 activity in TRAMP C1 cells. HepG2-C8 cells transfected with an antioxidant-response element (ARE)-luciferase vector were treated with F10, E10, curcumin and sulforaphane (SFN) to compare their effects on Nrf2-ARE pathways...
December 11, 2017: Chemical Research in Toxicology
Florence Daniela Berger, Shana J Sturla, Ryan W Kung, Tony Montina, Stacey D Wetmore, Richard A Manderville
Aromatic chemical carcinogens can undergo enzymatic transformations to produce a range of electrophilic species that attach covalently to the C8-site of 2'-deoxyguanosine (dG) to afford C8-dG adducts. The most studied C8-dG adducts are formed from arylamines and contain a N-linkage separating the dG from the C8-aryl moiety. Other carcinogenic species result in direct aryl ring attachment to the dG moiety, resulting in C-linked adducts. The resulting C-linked adducts have reduced conformational flexibility compared to the corresponding N-linked C8-dG adducts, which can alter their orientation in the DNA duplex...
November 29, 2017: Chemical Research in Toxicology
Sergio Manzetti
Parabens, phthalates, and perfluorinated compounds are pollutant compounds used in cosmetics, plastics, and fire-fighting foams. All three compounds have been studied over several years for toxicity mechanism; however, a clear view of their ability to bind to DNA has not been supplied empirically. In this work, a simulation study is done to reveal the interaction of three of these pollutants, bis(2-ethylhexyl)-phthalate (DEHP), butylparaben (BPRB), and the protonated form of perfluorooctanesulfonic acid (PFOS(H)), with DNA...
November 29, 2017: Chemical Research in Toxicology
Xiaoying Liu, Xiaoli Zou, Huangyuan Li, Zhenyu Zou, Jie Yang, Chenlu Wang, Shunhua Wu, Huidong Zhang
The abasic site is one the most common DNA lesion formed in cells, which induces severe blockage to DNA replication, and is highly mutagenic. We continue to use Gp90 exo-, the sole DNA polymerase from Pseudomonas aeruginosa phage PaP1, to study DNA replication encountering an abasic site lesion. Gp90 exo- can incorporate dNTPs opposite the abasic site, but extension past this site is extremely slow. Among four dNTPs, dATP is preferentially incorporated opposite the abasic site, consistent with the A-rule. The incorporation is independent of the identity of the nucleotide 5'- to the abasic site...
November 28, 2017: Chemical Research in Toxicology
Zachary T Bitzer, Reema Goel, Samantha M Reilly, Jonathan Foulds, Joshua Muscat, Ryan J Elias, John P Richie
The ever-evolving market of electronic cigarettes (e-cigarettes) presents a challenge for analyzing and characterizing the harmful products they can produce. Earlier we reported that e-cigarette aerosols can deliver high levels of reactive free radicals; however, there is little data characterizing the production of these potentially harmful oxidants. Thus, we have performed a detailed analysis of the different parameters affecting free radical production from e-cigarettes. Using a temperature controlled e-cigarette device and novel mechanism for reliably simulating e-cigarette usage conditions including coil activation and puff flow, we analyzed the effects of temperature, wattage, and e-liquid solvent composition of propylene glycol (PG) and glycerol (GLY) on radical production...
November 21, 2017: Chemical Research in Toxicology
Quan Yuan, Linda L Pearce, Jim Peterson
In aqueous media at neutral pH, the binding of two cyanide molecules per cobinamide can be described by two formation constants, Kf1 = 1.1 (±0.6) × 10(5) M(-1) and Kf2 = 8.5 (±0.1) × 10(4) M(-1), or an overall cyanide binding constant of ∼1 × 10(10) M(-2). In comparison, the cyanide binding constants for cobalamin and a fully oxidized form of cytochrome c oxidase, each binding a single cyanide anion, were found to be 7.9 (±0.5) × 10(4) M(-1) and 1.6 (±0.2) × 10(7) M(-1), respectively. An examination of the cyanide-binding properties of cobinamide at neutral pH by stopped-flow spectrophotometry revealed two kinetic phases, rapid and slow, with apparent second-order rate constants of 3...
November 21, 2017: Chemical Research in Toxicology
Zhi-Bin Tong, Ruili Huang, Yuhong Wang, Carleen Klumpp-Thomas, John Braisted, Zina Itkin, Paul Shinn, Menghang Xia, Anton Simeonov, David Gerhold
A chemical genomics 'Toxmatrix' method was developed to elucidate mechanisms of cytotoxicity using neuronal models. Quantitative high-throughput screening (qHTS) was applied to systematically screen each toxicant against a panel of 70 modulators, drugs or chemicals that act on a known target, to identify interactions that either protect or sensitize cells to each toxicant. Thirty-two toxicants were tested at 10 concentrations for cytotoxicity to SH-SY5Y human neuroblastoma cells, with results fitted to the Hill equation to determine an IC50 for each toxicant...
November 20, 2017: Chemical Research in Toxicology
Sandra Aurora Niño, Guadalupe Martel-Gallegos, Adriana Castro-Zavala, Benita Ortega-Berlanga, Juan Manuel Delgado, Hector Hernandez-Mendoza, E Romero-Guzman, Judith Rios-Lugo, Sergio Rosales-Mendoza, María Esther Jiménez-Capdeville, Sergio Zarazua
Chronic arsenic exposure during development is associated with alterations of chemical transmission and demyelination, which result in cognitive deficits and peripheral neuropathies. At cellular level, arsenic toxicity involves increased generation of reactive species that induce severe cellular alterations such as DNA fragmentation, apoptosis and lipid peroxidation. It has been proposed that arsenic-associated neurodegeneration could evolve to Alzheimer disease in later life.1,2 In this study, the effects of chronic exposure to inorganic arsenic (3 ppm by drinking water) in Wistar rats on the production and elimination of Amyloid-β (Aβ) were evaluated...
November 20, 2017: Chemical Research in Toxicology
Masahiro Akiyama, Yasuhiro Shinkai, Takamitsu Unoki, Ilseob Shim, Isao Ishii, Yoshito Kumagai
Cadmium (Cd) is an environmental electrophile that modifies protein nucleophiles, thereby modulating cellular signaling and toxicity. While reactive persulfides/polysulfides exhibit relatively high nucleophilic properties, their roles in the altered gene expression and toxicity caused by Cd remain unclear. Exposing primary mouse hepatocytes to Cd caused heat shock protein 70 (HSP70) and metallothionein (MT)-I/II to be upregulated and cytotoxicity to occur. These effects were blocked in the presence of polysulfide sodium tetrasulfide (Na2S4)...
November 20, 2017: Chemical Research in Toxicology
Mohammed Amali, Rosalind Jenkins, Xioali Meng, Lee Faulkner, Paul Whitaker, Daniel Peckham, B Kevin Park, Dean John Naisbitt
The risk of developing hypersensitivity to alternative antibiotics is a concern for penicillin hypersensitive patients and healthcare pro-viders. Herein we use piperacillin hypersensitivity as a model to explore the reactivity of drug-specific IgG against alternative β-lactam protein adducts. Mass spectrometry was used to show the drugs (amoxicillin, flucloxacillin, benzyl penicillin, aztreonam and pipera-cillin) bind to similar lysine residues on the protein carrier bovine serum albumin. However, the hapten-specific IgG antibodies found in piperacillin hypersensitive patient plasma did not bind to other β-lactam protein conjugates...
November 17, 2017: Chemical Research in Toxicology
George W Preston, Michelle Plusquin, Osman Sozeri, Karin van Veldhoven, Lilian Bastian, Tim S Nawrot, Marc Chadeau-Hyam, David H Phillips
Covalently modified blood proteins (e.g., serum albumin adducts) are increasingly being viewed as potential biomarkers via which the environmental causes of human diseases may be understood. The notion that some (perhaps many) modifications have yet to be discovered has led to the development of untargeted adductomics methods, which attempt to capture entire populations of adducts. One such method is fixed-step selected reaction monitoring (FS-SRM), which analyses distributions of serum albumin adducts via shifts in the mass of a tryptic peptide [Li et al...
November 17, 2017: Chemical Research in Toxicology
Liang Chi, Ridwan Mahbub, Bei Gao, Xiaoming Bian, Pengcheng Tu, Hongyu Ru, Kun Lu
As the primary active substance in tobacco, nicotine affects the activity of the central nervous system, and its effects are sex-dependent. There are complex interactions between the gut and brain, and the gut microbiome can influence neuronal activity and host behavior, with diverse chemical signaling being involved. However, it is unclear whether nicotine can affect the normal gut microbiome and associated chemical signaling of the gut-brain axis. Sex is an important factor that shapes the gut microbiome, but the role of sex in the interaction among nicotine, gut bacteria, and related metabolites remains unknown...
November 16, 2017: Chemical Research in Toxicology
Seda Onder, Alicia J Dafferner, Lawrence M Schopfer, Gaoping Xiao, Udaya Yerramalla, Ozden Tacal, Thomas A Blake, Rudolph C Johnson, Oksana Lockridge
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are irreversibly inhibited by organophosphorus pesticides through formation of a covalent bond with the active site serine. Proteins that have no active site serine, for example albumin, are covalently modified on tyrosine and lysine. Chronic illness from pesticide exposure is not explained by inhibition of AChE and BChE. Our goal was to produce a monoclonal antibody that recognizes proteins diethoxyphosphorylated on tyrosine. Diethoxyphosphate-tyrosine adducts for 13 peptides were synthesized...
November 14, 2017: Chemical Research in Toxicology
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