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Chemical Research in Toxicology

Adam Heller, Karalee Jarvis, Sheryl S Coffman
Pigment-grade titanium dioxide (TiO2) of 200-300 nm particle diameter is one of the most widely used submicron-sized particle materials. Inhaled and ingested TiO2 particles are known to enter the bloodstream, to be phagocytized by macrophages and neutrophils, to be inflammatory, and to activate the NLRP3 inflammasome. In this pilot study of 11 pancreatic specimens, 8 of the type 2 diabetic pancreas and 3 of the non-diabetic pancreas, we show that 110±70 nm average diameter TiO2 crystals abound in the type 2 diabetic pancreas, but not in the non-diabetic pancreas...
May 24, 2018: Chemical Research in Toxicology
Anna K Duell, James F Pankow, David H Peyton
E-liquids usually contain significant nicotine, which will exist primarily in two forms, monoprotonated and free-base the proportions are alterable through the effective pH of the medium. The fraction of nicotine in the free-base form is αfb , with 0 < αfb < 1. When dosed via aerosol, the two nicotine forms have different mechanisms and kinetics of delivery, as well as differing implications for harshness of the inhaled aerosol, so αfb is relevant regarding abuse liability. Previous attempts to determine αfb in electronic cigarette liquids and vapor have been flawed...
May 18, 2018: Chemical Research in Toxicology
Seda Onder, Lawrence M Schopfer, Ozden Tacal, Thomas A Blake, Rudolph C Johnson, Oksana Lockridge
Chronic illness from exposure to organophosphorus toxicants is hypothesized to involve modification of unknown proteins. Tyrosine in proteins that have no active site serine readily reacts with organophosphorus toxicants. We developed a monoclonal antibody, depY, that specifically recognizes diethoxyphospho-tyrosine in proteins and peptides, independent of the surrounding amino acid sequence. Our goal in the current study was to identify diethoxyphosphorylated proteins in human HEK293 cell lysate treated with chlorpyrifos oxon...
May 18, 2018: Chemical Research in Toxicology
Wenlin Yuan, Jun Chen, Hongren Huang, Zhihui Cai, Qinjie Ling, Feng Huang, Zhi Huang
Arsenic (As) is a well-known environmental pollutant,while arsenic trioxide (ATO) has been proven to be an effective treatment for acute promyelocytic leukemia, however, the mechanism underlying its dual effects is not fully understood.Embryonic stem cells (ESCs) appear properties of stemness and serve as a popular model to investigate epigenetic modifiers includingenvironmental pollutants.Herein, the effect of low dose ATO on differentiation were evaluatedin vitro using a mouse ESCs (mESCs) cell line, CGR8...
May 16, 2018: Chemical Research in Toxicology
Katerina Hruskova, Eliska Potuckova, Lukas Opalka, Tereza Hergeselova, Pavlina Haskova, Petra Kovarikova, Tomas Simůnek, Katerina Vavrova
Aroylhydrazone iron chelators such as salicylaldehyde isonicotinoyl hydrazone (SIH) protect various cells against oxidative injury and/or display antineoplastic activities. Previous studies have shown that a nitro-substituted hydrazone, namely, NHAPI, displayed markedly improved plasma stability, selective antitumor activity, and moderate antioxidant properties. In this study, we prepared four series of novel NHAPI derivatives and explored their iron chelation activities, anti- or pro-oxidant effects, protection against model oxidative injury in the H9c2 cell line derived from rat embryonic cardiac myoblasts, cytotoxicities to the corresponding noncancerous H9c2 cells, and antiproliferative activities against the MCF-7 human breast adenocarcinoma and HL-60 human promyelocytic leukemia cell lines...
May 16, 2018: Chemical Research in Toxicology
Alf Claesson, Alexander Minidis
Reactive metabolites are widely accepted as playing a pivotal role in causing idiosyncratic adverse drug reactions (IDR). However, much is unknown about the biological mechanisms of IDR although the initiating event in most cases is an attachment of a reactive intermediate to macromolecules leading to immune mediated responses. Reactive metabolites are also involved in many mutagenesis/ carcinogenesis events by reacting with DNA. Drug designers thus have all reasons to make large efforts to avoid making test compounds having a liability to generate reactive metabolites...
May 10, 2018: Chemical Research in Toxicology
Yaqin Liang, Anna L Lang, Jian Zhang, Jing Chen, Kai Wang, Liya Chen, Juliane I Beier, Yan Qian, Lu Cai
Obesity, usually caused by high fat diets (HFD), is a major public health issue worldwide, causing obesity associated cardiomyopathy. Moreover, the environmental toxicant vinyl chloride (VC) can exacerbate HFD-induced fatty liver disease. However, whether VC serves to enhance obesity-associated cardiomyopathy remains unclear. This study aims to investigate the interaction of western diet (WD) containing relatively low fat (42%) with VC on cardiac remodeling and its underling mechanisms. Adult male C57BL/6J mice were exposed to WD coinhalation of low-dose VC (<1 ppm/d) for 12 weeks...
May 10, 2018: Chemical Research in Toxicology
Charlotte G G M Pauwels, Walther N M Klerx, Jeroen L A Pennings, Agnes W Boots, Frederik Jan van Schooten, Antoon Opperhuizen, Reinskje Talhout
The WHO Study Group on Tobacco Product Regulation (TobReg) advised regulating and lowering toxicant levels in cigarette smoke. Aldehydes are one of the chemical classes on the TobReg smoke toxicants priority list. To provide insight in factors determining aldehyde yields, the levels of 12 aldehydes in mainstream cigarette smoke of 11 Dutch brands were quantified. Variations in smoking behavior and cigarette design affecting human exposure to aldehydes were studied by using four different machine testing protocols...
May 4, 2018: Chemical Research in Toxicology
Paul D Leeson
A database containing maximum daily doses of 1841 marketed oral drugs was used to examine the influence of physicochemical properties on dose and hepatotoxicity (drug induced liver injury, DILI). Drugs in the highest ~20% dose range had significantly reduced mean lipophilicity and molecular weight, increased fractional surface area, increased % of acids and decreased % of bases, versus drugs in the lower ~60% dose range. Drugs in the ~20-40% dose range had intermediate mean properties, similar to the mean values for the full drug set...
May 3, 2018: Chemical Research in Toxicology
Keith Fraser, Dylan M Bruckner, Jonathan S Dordick
Adverse drug reactions (ADRs), particularly those that result in drug-induced liver injury (DILI) is a major cause of drug failure in clinical trials and drug withdrawals. Hepatotoxicity-mediated drug attrition occurs despite substantial investments of time and money in developing cellular assays, animal models and computational models to predict its occurrence in humans. Underperformance in predicting hepatotoxicity associated with drugs and drug candidates has been attributed to existing gaps in our understanding of the mechanisms involved in driving hepatic injury after these compounds perfuse and are metabolized by the liver...
May 3, 2018: Chemical Research in Toxicology
Angélica Bianchini Sanchez, Camila Carrião Machado Garcia, Florêncio Porto Freitas, Guilherme Lopes Batista, Fernando Silva Lopes, Victor Henrique Carvalho, Graziella Eliza Ronsein, Ivano Gebhardt Rolf Gutz, Paolo Di Mascio, Marisa Helena Gennari de Medeiros
Air pollution is a major environmental risk for human health. Acetaldehyde is present in tobacco smoke and vehicle exhaust. In this study, we show that [13C2]-acetaldehyde induces DNA modification with the formation of isotopically labeled 1,N2-propano-2´-deoxyguanosine adducts in the brain and lungs of rats exposed to concentrations of acetaldehyde found in the atmosphere of megacities. The adduct with the addition of two molecules of isotopically labeled acetaldehyde [13C4]-1,N2-propanodGuo was detected in the lung and brain tissues of exposed rats by micro-HPLC/MS/MS...
April 30, 2018: Chemical Research in Toxicology
Reema Goel, Zachary T Bitzer, Samantha M Reilly, Jonathan Foulds, Joshua Muscat, Ryan J Elias, John P Richie
Cigarette smoke is a major exogenous source of free radicals, and the resulting oxidative stress is one of the major causes of smoking-caused diseases. Yet, many of the factors that impact free radical delivery from cigarettes remain unclear. In this study, we machine-smoked cigarettes and measured the levels of gas- and particulate-phase radicals by electron paramagnetic resonance (EPR) spectroscopy using standardized smoking regimens (International Organization of Standardization (ISO) and Canadian Intense (CI)), puffing parameters and tobacco blends...
April 27, 2018: Chemical Research in Toxicology
Natalie C Sadler, Bobbie-Jo M Webb-Robertson, Therese R Clauss, Joel G Pounds, Richard Corley, Aaron T Wright
Cytochrome P450 monooxygenase (P450) enzymes metabolize critical endogenous chemicals and oxidize nearly all xenobiotics. Dysregulated P450 activities lead to altered capacity for drug metabolism and cellular stress. The effects of mixed exposures on P450 expression and activity are variable and elusive. A high-fat diet (HFD) is a common exposure that results in obesity and associated pathologies including hepatotoxicity. Herein, we report the effects of cigarette smoke on P450 activities of normal weight and HFD induced obese mice...
April 24, 2018: Chemical Research in Toxicology
Xiaotong Qin, Ying Peng, Jiang Zheng
Physcion (1,8-dihydroxy-3-methoxy-6-methyl-9,10-anthracenedione) is a bioactive component found in Polygoni Multiflori Radix (PMR) which has been widely used as traditional Chinese medicine. Unfortunately, studies showed hepatotoxicity of PMR during its clinical use. The mechanisms of its toxic action remain unknown. The major objectives of this study were to characterize oxidative metabolites of physcion in vitro and in vivo and to determine the electrophilicity of the parent compound and its oxidative metabolites...
April 18, 2018: Chemical Research in Toxicology
Cassandra Deering-Rice, Nam Nguyen, Zhenyu Lu, James Cox, Darien Shapiro, Erin G Romero, Virginia K Mitchell, Katherine L Burrell, John M Veranth, Christopher A Reilly
Wood/biomass smoke particulate materials (WBSPM) are pneumotoxic, but mechanisms by which these materials affect lung cells are not fully understood. We previously identified transient receptor potential (TRP) ankyrin-1 as a sensor for electrophiles in WBSPM and hypothesized that other TRP channels expressed by lung cells might also be activated by WBSPM, contributing to pneumotoxicity. Screening TRP channel activation by WBSPM using calcium flux assays revealed TRPV3 activation by materials obtained from burning multiple types of wood under fixed conditions...
April 16, 2018: Chemical Research in Toxicology
Ji Jiang, Lok Ming Tam, Pengcheng Wang, Yinsheng Wang
Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response signaling pathway is a major mechanism for the cellular defense against oxidative stress. Arsenite, a widespread contaminant in drinking water, is known to induce oxidative stress and activate Nrf2-dependent signaling pathway through stabilization of Nrf2 protein by inhibiting its ubiquitination via the Cul3-Rbx1-Keap1 (cullin 3, RING-box 1, and Kelch-like ECH-associated protein 1) E3 ubiquitin ligase and its degradation by the 26S proteasome, though the underlying mechanism remains elusive...
April 16, 2018: Chemical Research in Toxicology
Kazutaka Hirakawa, Dongyan Ouyang, Yuko Ibuki, Shiho Hirohara, Shigetoshi Okazaki, Eiji Kono, Naohiro Kanayama, Jotaro Nakazaki, Hiroshi Segawa
Photodynamic therapy (PDT) is a less-invasive treatment for cancer through the administration of less-toxic porphyrins and visible-light irradiation. Photosensitized damage of biomacromolecules through singlet oxygen (1 O2 ) generation induces cancer cell death. However, a large quantity of porphyrin photosensitizer is required, and the treatment effect is restricted under a hypoxic cellular condition. Here we report the phototoxic activity of P(V)porphyrins; dichloroP(V)tetrakis(4-methoxyphenyl)porphyrin (CLP(V)TMPP), dimethoxyP(V)tetrakis(4-methoxyphenyl)porphyrin (MEP(V)TMPP), and diethyleneglycoxyP(V)tetrakis(4-methoxyphenyl)porphyrin (EGP(V)TMPP)...
April 16, 2018: Chemical Research in Toxicology
Chih-Wei Liu, Xu Tian, Hadley J Hartwell, Jiapeng Leng, Liang Chi, Kun Lu, James A Swenberg
Genomic instability caused by DNA-protein crosslink (DPCs)-induced DNA damage is implicated in disease pathogenesis, aging and cancer development. The covalent linkages between DNA and protein are induced by chemical reactions catalyzed by the endogenous metabolic intermediates and exogenous agents such as aldehydes, chemotherapeutic agents, and ionizing radiation. Formaldehyde has been classified as a genotoxic carcinogen. In addition, endogenous formaldehyde-induced DPCs may increase the risks of bone marrow toxicity and leukemia...
April 13, 2018: Chemical Research in Toxicology
Erik S Carlson, Pramod Upadhyaya, Peter W Villalta, Bin Ma, Stephen S Hecht
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are carcinogenic in animal models and are believed to play an important role in human lung carcinogenesis in cigarette smokers. Cytochrome P450-mediated metabolism of these tobacco-specific nitrosamines produces reactive species that alkylate DNA in the form of pyridyloxobutyl (POB)- or pyridylhydroxybutyl (PHB)-DNA adducts. Understanding the formation mechanism and overall levels of these adducts can potentially enhance cancer prevention methods through the identification of particularly susceptible smokers...
April 13, 2018: Chemical Research in Toxicology
Alejandra Monroy-Arreola, Noe Duran-Figueroa, Silvia Mendez-Flores, Judith Dominguez-Cherit, Joel Watkinson, Agustin Badillo-Corona, Paul Whitaker, Dean Naisbitt, Luis Castrejon Flores
Dysregulation in the expression of microRNAs (miRNAs), single stranded RNAs which regulate gene expression, has been associated with diseases such as Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN), although their cellular origin has not been explored. Thus, the focus of this work was to study expression patterns of reported miRNAs involved in T - cell activation following drug-specific stimulation in peripheral blood mononuclear cells (PBMCs) and drug specific CD4+ T-cell clones (TCC) from patients with different cutaneous manifestations of delayed-type drug hypersensitivity reactions...
April 12, 2018: Chemical Research in Toxicology
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