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Chemical Research in Toxicology

Florence Daniela Berger, Richard A Manderville, Shana J Sturla
Aromatic chemicals can undergo metabolic activation to afford electrophilic species that react at the C8-site of 2'-deoxyguanosine (dG) to generate bulky C8-dG adducts as a basis of initiating carcinogenesis. These DNA lesions have served as models to understand the mechanism of frameshift mutagenesis, especially within CG-dinucleotide repeat sequences, such as NarI (5'-GGCXCC-3', where X = C8-dG adduct). However, there is still limited capacity to predict the likelihood of mutation arising within particular contexts and hence chemistry-based strategies are needed for probing relationships between nucleic acid sequence and structure with replication errors...
February 20, 2019: Chemical Research in Toxicology
Hiroshi Kasai, Yuya Kawasaki, Kazuaki Kawai
After thymidine (dT) was treated with a Fenton-type reagent and further incubated for a long period (6 days) under physiological conditions (37°C, pH 7.4), a new product, named dT*, was detected by HPLC in addition to the free thymine base and the known oxidative dT damage, 5-formyl-2'-deoxyuridine (f5dU). dT* was found to be formed from f5dU. The structure of dT* was determined to be 3-amino-2-carbamoyl-2-propenal-N3-2'-deoxyriboside, a pyrimidine ring-opened product from f5dU, on the basis of 1H- and 13C-NMR analyses and the mass spectrum...
February 20, 2019: Chemical Research in Toxicology
Zhe Li, Tom E Forshaw, Reetta J Holmila, Stephen A Vance, Hanzhi Wu, Leslie B Poole, Cristina M Furdui, S Bruce King
Redox mediated protein modifications control numerous processes in both normal and disease metabolism. Protein sulfenic acids, formed from the oxidation of protein cysteine residues, play a critical role in thiol-based redox signaling. The reactivity of protein sulfenic acids requires their identification through chemical trapping and this paper describes the use of the triphenyl phosphonium ion to direct known sulfenic acid traps to the mitochondria, a verified source of cellular reactive oxygen species. Coupling of the triphenyl phosphonium (TPP) group with the 2, 4-(dioxocyclohexyl)propoxy (DCP) unit and the bicyclo[6...
February 20, 2019: Chemical Research in Toxicology
Jordan M Chapman, Joelle K Muhlemann, Sheena R Gayomba, Gloria K Muday
Reactive Oxygen Species (ROS) have recently been shown to regulate plant growth and development. ROS are kept at low levels in cells to prevent oxidative damage, allowing them to be effective signaling molecules upon increased synthesis. In plants and animals, NADPH Oxidase/Respiratory Burst Oxidase proteins provide localized ROS bursts to regulate growth, developmental processes, and stress responses. This review details ROS production via respiratory burst homolog enzymes in the context of plant development and stress responses and defines the locations and tissues in which members of this family function in the model plant Arabidopsis thaliana...
February 20, 2019: Chemical Research in Toxicology
Hui Li, Zhengyu Zhang, Xiaojing Yang, Xu Mao, Ying Wang, Jian Wang, Ying Peng, Jiang Zheng
Nitrofurantoin (NFT) is a widely used antimicrobial agent in the treatment of specific urinary tract infections (UTIs). Many adverse effects associated with NFT use have been reported, including hepatotoxicity. A structure-toxicity relationship study was performed to gain the insight into the mechanisms of toxic action of NFT. The toxic effects of NFT and its nine analogues or constituent moieties (1-9) designed and synthesized by structural manipulation of NFT were evaluated in rat liver microsomes and primary rat hepatocytes...
February 19, 2019: Chemical Research in Toxicology
Runhan Yu, Youngchang Kim, Natalia Maltseva, Philip Braunstein, Andrzej Joachimiak, Lizbeth Hedstrom
Reactive nitrogen species (RNS) are produced during infection and inflammation and the effects of these agents on proteins, DNA and lipids are well recognized. In contrast, the effects of RNS damaged metabolites are less appreciated. 5-Amino-3-β-(D-ribofuranosyl)-3 H-imidazo-[4,5-d][1,3]oxazine-7-one (oxanosine) and its nucleotides are products of guanosine nitrosation. Here we demonstrate that oxanosine monophosphate (OxMP) is a potent reversible competitive inhibitor of IMPDH. The value of Ki varies from 50 to 340 nM among IMPDHs from five different organisms...
February 12, 2019: Chemical Research in Toxicology
Cassandra J Meakin, Elizabeth M Martin, John T Szilagyi, Leena A Nylander-French, Rebecca C Fry
Prenatal exposure to inorganic arsenic (iAs) has been associated with adverse developmental and reproductive outcomes. These outcomes may be tied to altered functionality of nuclear transcription factors such as the glucocorticoid receptor (GR) in the placenta and associated gene expression. The GR pathway is integral for proper fetal and placental development, and perturbations in this pathway may underlie observed associations between prenatal iAs exposure and adverse birth outcomes. We therefore set out to investigate whether iAs modulates the GR signaling pathway in placental cells...
February 12, 2019: Chemical Research in Toxicology
Yupeng Li, Bin Ma, Qing Cao, Silvia Balbo, Lijiao Zhao, Pramod Upadhyaya, Stephen S Hecht
The tobacco-specific carcinogens N´-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) require metabolic activation to exert their carcinogenicity. NNN and NNK are metabolized to the same reactive diazonium ions, which alkylate DNA forming pyridyloxobutyl (POB) DNA base and phosphate adducts. We have characterized the formation of both POB DNA base and phosphate adducts in NNK-treated rats, and the formation of POB DNA base adducts in NNN-treated rats. However, POB DNA phosphate adducts in NNN-treated rats are still uncharacterized...
February 11, 2019: Chemical Research in Toxicology
Toshiyuki Nakamura, Miho Hirakawa, Yoshimasa Nakamura, Akari Ishisaka, Noritoshi Kitamoto, Akira Murakami, Yoji Kato
Benzyl isothiocyanate (BITC), a dietary isothiocyanate (ITC) derived from cruciferous vegetables, has anticancer properties. It is believed that the ITC moiety (-N=C=S) that reacts predominantly with thiol compounds plays a central role in triggering the activities resulting from these properties. Recent studies have demonstrated that ITCs also covalently modify amino moieties in a protein. In this study, we examined the chemical reaction between BITC and the aminophospholipid, phosphatidylethanolamine (PE), in the cell membrane or lipoprotein particle...
February 8, 2019: Chemical Research in Toxicology
Elizabeth Huerta-Garcia, Maria Del Pilar Ramos-Godinez, Alejandro Lopez-Saavedra, Ernesto Alfaro-Moreno, Nancy Patricia Gomez-Crisostomo, Zaira Colin-Val, Rebeca López-Marure
Titanium dioxide nanoparticles (TiO2 NPs) are widely used for industrial and commercial applications. Once inside the body, they translocate into the bloodstream and reach different areas of the cardiovascular system including the heart, increasing the risk of developing cardiovascular diseases; consequently, the investigation of their interaction with cardiac cells is required. We previously showed that TiO2 NPs are internalized by H9c2 rat cardiomyoblasts and here we examined the molecular mechanisms underlying this process...
February 7, 2019: Chemical Research in Toxicology
Xueshu Li, Xianai Wu, Kevin M Kelly, Peter Veng-Pedersen, Hans-Joachim Lehmler
Exposure to polychlorinated biphenyls (PCBs) has been implicated in adverse human health effects, including developmental neurotoxicity. Several neurotoxic PCBs are chiral and undergo atropisomeric enrichment in vivo due to atropselective metabolism by cytochrome P450 enzymes. Here we study how the liver-specific deletion of the cytochrome P450 reductase (cpr) gene alters the toxicokinetics of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice. Male and female mice with a liver-specific dele-tion of cpr (KO) and congenic wild-type (WT) mice were exposed to a single oral dose of racemic PCB 136 (6...
February 7, 2019: Chemical Research in Toxicology
Obed Adu Gyamfi, Nesta Bortey-Sam, Sari B Mahon, Matthew Brenner, Gary A Rockwood, Brian Alexander Logue
The direct analysis of cyanide (HCN or CN- inclusively symbolized as CN) to confirm exposure has major limitations due to cyanide's volatility, reactivity, and short half-life in biological fluids. These limitations have led to the exploration of cyanide detoxification products for indirect verification of cyanide exposure. Although cyanide interacts strongly with sulfur-containing molecules, to date, biomarkers resulting from the interaction of cyanide with glutathione (GSH; i.e., a biologically abundant sulfur-donating biomolecule) have yet to be discovered...
February 6, 2019: Chemical Research in Toxicology
Adam V Wisnewski, Ala F Nassar, Jian Liu, Dhimiter Bello
Biomonitoring methylene dipheny diisocyanate (MDI) in urine may be useful in industrial hygiene and exposure surveillance approaches toward disease (occupational asthma) prevention, and in understanding pathways by which internalized chemical is excreted. We explored possible urine biomarkers of MDI exposure in mice after respiratory tract exposure to MDI, as glutathione (GSH) reaction products (MDI-GSH), and after skin exposure to MDI dissolved in acetone. LC-MS analyses of urine identified a unique 543.29 m/z [M+H]+ ion from MDI exposed mice, but not controls...
February 6, 2019: Chemical Research in Toxicology
Runhui Liang, Shanshan Sun, Guanheng Huang, Ming-De Li
Naproxen is a nonsteroidal anti-inflammatory drug that exhibits phototoxic side effects in humans, but the mechanism of phototoxicity is ambiguous. To uncover photophysical and photochemical reaction processes of naproxen, femtosecond to nanosecond transient absorption spectroscopies were employed to directly detect excited and transient states of naproxen upon UV irradiation in pure acetonitrile, acetonitrile: water 1:1 and acetonitrile: PBS 1:1 solutions. The transient absorption data together with time-dependent density functional theory analysis-predicted absorption spectra of the selected intermediates was integrated to elucidate photochemical mechanisms for reactions of naproxen in different solutions...
February 6, 2019: Chemical Research in Toxicology
Abigail F Scott, Christopher A Reilly
Air pollutants from burning wood and biomass pose serious human health risks. Recent discoveries link the chemistry of smoke emissions with biochemical sensors and biological effect mediators. Strategic thinking of complex underlying factors is needed to protect people from harm.
February 5, 2019: Chemical Research in Toxicology
Kevin D Siegenthaler, Carolyn S Sevier
The concept that reactive oxygen species (ROS) are primarily toxic, mitochondria-generated molecules has persisted for decades. Here we highlight the emerging complexity for ROS-based events, emphasizing the evolving importance of the endoplasmic reticulum as a source and platform for redox signaling.
February 5, 2019: Chemical Research in Toxicology
Yumi Abiko, Yumi Nakai, Nho Cong Luong, Christopher L Bianco, Jon M Fukuto, Yoshito Kumagai
We previously reported that 9,10-phenanthraquinone (9,10-PQ), an atmospheric electron acceptor, undergoes redox cycling with dithiols as electron donors, resulting in the formation of semiquinone radicals and monothiyl radicals; however, monothiols have little reactivity. Because persulfide and polysulfide species are highly reducing, we speculate that 9,10-PQ might undergo one-electron reduction with these reactive sulfides. In the present study, we explored the redox cycling capability of a variety of quinone-related electron acceptors, including 9,10-PQ, during interactions with the hydropersulfide Na2 S2 and its related polysulfides...
February 5, 2019: Chemical Research in Toxicology
Su Guo, Jiapeng Leng, Ying Tan, Nathan E Price, Yinsheng Wang
Quantitative measurement of DNA adducts in carcinogen-exposed cells provides the information about the frequency of formation and the rate of removal of DNA lesions in vivo, which yields insights into the initial events of mutagenesis. Metabolic activation of tobacco-specific nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its reduction product 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), leads to pyridyloxobutylation and pyridylhydroxybutylation of DNA. In this study, we employed a highly robust nanoflow liquid chromatography-nanoelectrospray ionization-tandem mass spectrometry (nLC-nESI-MS/MS) coupled with the isotope-dilution method, for simultaneous quantification of O6 -[4-(3-pyridyl)-4-hydroxylbut-1-yl]-2'-deoxyguanosine ( O6 -PHBdG) and O2 - and O4 -[4-(3-pyridyl)-4-hydroxylbut-1-yl]-thymidine ( O2 -PHBdT and O4 -PHBdT)...
February 4, 2019: Chemical Research in Toxicology
Anqi Shan, Mengxue Li, Xuejun Li, Yaoyan Li, Mengfan Yan, Ping Xian, Ying Chang, Xi Chen, Nai-Jun Tang
Polybrominated diphenyl ethers (PBDEs) have been reported to exert reproductive endocrine toxicity, but the mechanisms for this process remain unclear. Currently available studies have concentrated on the enzymatic reactions during steroidogenesis, but the results are not consistent. In this study, we explored the effects of 2,2',4,4'-tertrabromodiphenyl ether (BDE-47) on progesterone biosynthesis and the potential mechanisms in human placental choriocarcinoma cells. The results showed that BDE-47 decreased progesterone production in a dose-dependent manner but had no effect on key enzymes (Cyp11a1 and 3β-HSD)...
February 4, 2019: Chemical Research in Toxicology
Gabriela Chaufan, Camila Galvano, Mariela Nieves, Marta Dolores Mudry, Maria Del Carmen Rios de Molina, Nancy Beatriz Andrioli
The fungicide agents are a key component in the fruits and vegetables production. The Iprodione residues is one of the pesticide more frequently found in food products. The available data about the cytotoxicity of iprodione and its metabolites are scarce and do not allow to characterize its genotoxic potential and define the risk assessment .The human larynx epidermoid carcinoma cell line (HEp-2) it has been shown to be sensitive to the toxic effects of xenobiotics of different origin and have been often used in citotoxicity and genotoxicity studies...
January 31, 2019: Chemical Research in Toxicology
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