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Chemical Research in Toxicology

Sonia Emanuele, Antonella D'Anneo, Giuseppe Calvaruso, Cesare Cernigliaro, Michela Giuliano, Marianna Lauricella
The intracellular redox state in the cell depends on the balance between the level of reactive oxygen species (ROS) and the activity of defensive systems including antioxidant enzymes. This balance is a dynamic process that can change in relation to many factors and/or stimuli induced within the cell. ROS production is derived from physiological metabolic events. For instance, mitochondria represent the major ROS sources during oxidative phosphorylation, but other systems, such as NADPH oxidase or specific enzymes in certain metabolisms, may account for ROS production as well...
March 7, 2018: Chemical Research in Toxicology
Andrea A Cronican, Kristin L Frawley, Erin P Straw, Elisenda Lopez-Manzano, Hirunwut Praekunatham, Jim Peterson, Linda Lorraine Pearce
Four cobalt-containing macrocyclic compounds previously shown to ameliorate cyanide toxicity have been comparatively evaluated with an acute sub-lethal toxicity model in conscious (un-anesthetized) adult male Swiss-Webster mice. All of the compounds (the cobalt-corrins cobalamin and cobinamide, a cobalt-porphyrin, plus a cobalt-Schiff base macrocycle) given 5 min prior to the toxicant dose significantly decreased the righting-recovery time of cyanide-intoxicated mice, but the doses required for maximal antidotal effect varied...
March 7, 2018: Chemical Research in Toxicology
Georgia Menounou, Giorgia Giacometti, Roberta Scanferlato, Paolo Dambruoso, Anna Sansone, Itziar Tueros, Javier Amezaga, Chryssostomos Chatgilialoglu, Carla Ferreri
Docosahexaenoic acid (DHA) is a semi-essential polyunsaturated fatty acid (PUFA) for eukaryotic cells, found in natural sources such as fish and algal oils and widely used as ingredient for omega-3 containing foods or supplements. DHA effects are connected to its natural structure with six cis double bonds, but geometrical monotrans isomers can be formed during distillation or deodorization processes, as an unwanted event that alters molecular characteristics and annihilates health benefits. The characterization of the six monotrans DHA regioisomers is an open issue to address for analytical, biological and nutraceutical applications...
February 27, 2018: Chemical Research in Toxicology
Sharon Elizabeth Murphy, Linda von Weymarn, Marc Parenteau, Irina Stepanov, Maarit Tiirikainen, Loic LeMarchand, Sungshim L Park
At similar smoking levels African American's lung cancer risk is as much as twice that of whites. We hypothesized that racial/ethnic differences in UDP-glucuronosyltransferase (UGT)-catalyzed glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a detoxication pathway for the tobacco-specific lung carcinogen NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), may contribute to this variable risk. UGT2B10 catalyzes NNAL N-glucuronidation and a UGT2B10 splice variant is common among African Americans...
February 20, 2018: Chemical Research in Toxicology
Tung Xuan Trinh, Jang-Sik Choi, Hyunpyo Jeon, Hyung-Gi Byun, Tae Hyun Yoon, Jongwoon Kim
Quantitative structure-activity relationship (QSAR) models for nanomaterials (nano-QSAR) were developed to predict the cytotoxicity of 20 different types of multi-walled carbon nanotubes (MWCNTs) to human lung cells by using quasi-SMILES. The optimal descriptors, recorded as quasi-SMILES, were encoded to represent the physicochemical properties and experimental conditions for the MWCNTs from 276 data records collected from previously published studies. The qua-si-SMILES used to build the optimal descriptors were (i) diameter, (ii) length, (iii) surface area, (iv) in vitro toxicity assay, (v) cell line, (vi) exposure time, and (vii) dose...
February 14, 2018: Chemical Research in Toxicology
Toru Usui, Lee Faulkner, John Farrell, Neil French, Ana Alfirevic, Munir Pirmohamed, B Kevin Park, Dean John Naisbitt
It is unclear whether priming of naïve T cells to drugs is detectable in healthy human donors expressing different HLA alleles. Thus, we examined T cell priming with drugs associated with HLA risk alleles and control compounds in 14 HLA-typed donors. Nitroso sulfamethoxazole & piperacillin activated T cells from all donors, whereas responses to carbamazepine and oxypurinol were only seen in donors expressing HLA-B*15:02 and HLA-B*58:01, respectively. Weak flucloxacillin-specific T cell responses were detected in donors expressing HLA-B*57:01 and HLA-B*58:01...
February 13, 2018: Chemical Research in Toxicology
Michael Goettel, Reinhard Niessner, Max Scherer, Gerhard Scherer, Nikola Pluym
A preceding untargeted metabolic fingerprinting approach in our lab followed by a targeted fatty acid analysis revealed alterations in the arachidonic acid metabolism in samples derived from a diet-controlled smoking cessation study in which compliant subjects (N=39) quit smoking at baseline and were followed over the course of three months. Consequently, urinary eicosanoids were determined by means of a validated LC-MS/MS method. A significant decrease was obtained for the prostaglandins PGF2α, 8-iso-PGF2α, thromboxane 2,3-d-TXB2 and leukotriene E4 upon quitting smoking...
February 5, 2018: Chemical Research in Toxicology
Sarah C Shuck, Gerald E Wuenschell, John Stephen Termini
Methylglyoxal (MG) is a highly reactive electrophile produced endogenously as a byproduct of glucose metabolism and protein catabolism, and exogenously as a food contaminant. MG reacts spontaneously with proteins, lipids and nucleic acids to form advanced glycation end products (AGEs), modifying or inhibiting their function. Protein AGEs are associated with pathological complications of diabetes, cancer, and neurodegenerative diseases, while the physiological impact of DNA, RNA, and lipid AGE formation is less well explored...
January 24, 2018: Chemical Research in Toxicology
Na Le Dang, Tyler B Hughes, Grover Paul Miller, S Joshua Swamidass
Cytochromes P450 (CYPs) oxidize alkylated amines commonly found in drugs and other biologically active molecules, splitting them into an amine and an aldehyde. Metabolic studies usually neglect to report or investigate aldehydes, even though they can be toxic. It is assumed that they are efficiently detoxified into carboxylic acids and alcohols. Nevertheless, some aldehydes are reactive and escape detoxification pathways to cause adverse events by forming DNA and protein adducts. Herein, we modeled N-dealkylations that produce both amine and aldehyde metabolites and then predicted the reactivity of the aldehyde...
January 22, 2018: 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
Shana J Sturla
No abstract text is available yet for this article.
February 19, 2018: 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)-tetrahydro-thiopyran-4-one (F10) and (3E,5E)-3,5-bis-(3,4,5-trimethoxy-benzylidene)-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...
February 19, 2018: Chemical Research in Toxicology
Zhi-Bin Tong, Ruili Huang, Yuhong Wang, Carleen A Klumpp-Thomas, John C Braisted, Zina Itkin, Paul Shinn, Menghang Xia, Anton Simeonov, David L 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...
February 19, 2018: Chemical Research in Toxicology
Shana J Sturla
No abstract text is available yet for this article.
January 16, 2018: Chemical Research in Toxicology
Florence D 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...
January 16, 2018: Chemical Research in Toxicology
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