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Chemical Research in Toxicology

Nicole M Antczak, Alice R Walker, Hannah R Stern, Emmett M Leddin, Carl Palad, Timothy A Coulther, Rebecca J Swett, Gerardo Andres Cisneros, Penny J Beuning
Specialized DNA damage-bypass Y-family DNA polymerases contribute to cancer prevention by providing cellular tolerance to DNA damage that can lead to mutations and contribute to cancer progression by increasing genomic instability. Y-family polymerases can also bypass DNA adducts caused by chemotherapy agents. One of the four human Y-family DNA polymerases, DNA polymerase (pol) kappa has been shown to be specific for bypass of minor groove adducts and inhibited by major groove adducts. In addition, mutations in the gene encoding pol kappa are associated with different types of cancers as well as with chemotherapy responses...
July 13, 2018: Chemical Research in Toxicology
Marcin Dyba, Brandon Da Silva, Heidi Coia, Yanqi Hou, Sumire Noguchi, Jishen Pan, Deborah Berry, Karen Creswell, Jacek Krzeminski, Dhimant Desai, Shantu Amin, David C H Yang, Fung-Lung Chung
Lipid peroxidation (LPO) of polyunsaturated fatty acids (PUFAs) is an endogenous source of α,β-unsaturated aldehydes that react with DNA producing a variety of cyclic adducts. The mutagenic cyclic adducts, specifically those derived from oxidation of ω-6 PUFAs, may contribute to the cancer promoting activities associated with ω-6 PUFAs. (E)-4-Hydroxy-2-nonenal (HNE) is a unique product of ω-6 PUFAs oxidation. HNE reacts with deoxyguanosine (dG) yielding mutagenic 1,N2-propanodeoxyguanosine adducts (HNE-dG)...
July 12, 2018: Chemical Research in Toxicology
Claudia Luckert, Albert Braeuning, Georges de Sousa, Sigrid Durinck, Efrosini S Katsanou, Parthena Konstantinidou, Kyriaki Machera, Emanuela S Milani, Ad A C M Peijnenburg, Roger Rahmani, Andreja Rajkovic, Deborah Rijkers, Anastasia Spyropoulou, Marianna Stamou, Geert Stoopen, Shana Sturla, Bernd Wollscheid, Nathalie Zucchini-Pascal, Alfonso Lampen
Adverse outcome pathways (AOPs) describe causal relationships between molecular perturbation and adverse cellular effects and are being increasingly adopted for linking in vitro mechanistic toxicology to in vivo data from regulatory toxicity studies. In this work, a case study was performed by developing a bioassay toolbox to assess key events in the recently proposed AOP for chemically induced liver steatosis. The toolbox is comprised of in vitro assays to measure nuclear receptor activation, gene and protein expression, lipid accumulation, mitochondrial respiration, and formation of fatty liver cells...
July 11, 2018: Chemical Research in Toxicology
Reema Goel, Zachary T Bitzer, Samantha M Reilly, Gurkirat Bhangu, Neil Trushin, Ryan J Elias, Jonathan Foulds, Joshua Muscat, John P Richie
The addition of charcoal in cigarette filters may be an effective means of reducing many toxicants from tobacco smoke. Free radicals are a highly reactive class of oxidants abundant in cigarette smoke, and, here, we evaluated the effectiveness of charcoal to reduce free radical delivery by comparing radical yields from commercially available cigarettes with and without charcoal-infused filters, and by examining the effects of incorporating charcoal into conventional cigarette filters on radical production. Commercial cigarettes containing charcoal filters produced 40% fewer gas-phase radicals than regular cellulose acetate filter cigarettes when smoked using the International Organization of Standardization (ISO, p= 0...
July 6, 2018: Chemical Research in Toxicology
Yu-Chou Chi, Shou-Lun Lee, Yung-Ping Lee, Ching-Long Lai, Shih-Jiun Yin
Alcohol dehydrogenase (ADH) is the principal enzyme responsible for the metabolism of ethanol. Human ADH constitutes a complex family of isozymes and allozymes with striking variation in kinetic properties and tissue distribution. The liver and the gastrointestinal tract are the major sites for first-pass metabolism (FPM). The quantitative contributions of ADH isozymes and ethnically distinct allozymes to cellular ethanol metabolism remain poorly understood. To address this issue, kinetic mechanism and the steady-state full-rate equations for recombinant human class I ADH1A, ADH1B (including allozymes ADH1B1, ADH1B2, and ADH1B3), ADH1C (including allozymes ADH1C1 and ADH1C2), class II ADH2, and class IV ADH4 were determined by initial velocity, product inhibition, and dead-end inhibition experiments in 0...
July 5, 2018: Chemical Research in Toxicology
Wan Chan, Sum-Kok Wong, Weiwei Li
1-Nitropyrene (1NP) level is closely associated with the mutagenicity of diesel exhaust and is being used as the marker molecule for diesel exhaust. Thus, quantitation of exposure to 1NP may provide an efficient method for biomonitoring human exposure to diesel exhaust and risk assessment. Using ultra-performance liquid chromatography coupled with fluorescence or tandem mass spectrometric detection methods, we quantitated and compared in this study the DNA and protein adducts of 1NP in internal organs of 1NP-exposed rats...
July 3, 2018: Chemical Research in Toxicology
Li Ya Ma, Shu Hao Zhang, Jing Jing Zhang, Ai Ping Zhang, Na Li, Xin Qiang Wang, Qian Qian Yu, Hong Yang
Jasmonic acid (JA) (or methyl-jasmonic acid, MeJA) is one of the important regulators for plant growth, development and defense to environmental stresses. But how JA is involved in mediation of pesticide accumulation and degradation in plants is largely unknown. This study investigated the contribution of MeJA to detoxification and degradation of isoproturon residues in wheat (Triticum aestivum). Wheat plants were exposed to 4 mg kg-1 isoproturon (environmental realistic concentration). The growth and chlorophyll concentration were reduced, while the electrolyte permeability in plants was enhanced...
July 3, 2018: Chemical Research in Toxicology
Jiayin Dai
The reduced transcriptomic approach allows full dose range testing of hundreds of chemicals or mixtures using human cells or zebrafish embryos. Points of departure of genes and pathways can be used for potency ranking and to classify chemicals by disrupted biological pathways.
July 3, 2018: Chemical Research in Toxicology
Sonia Rebollo Ramirez, Sina Krokowski, Damian Lobato-Márquez, Michael Thomson, Ivana Pennisi, Serge Mostowy, Gerald Larrouy-Maumus
Antimicrobial resistance is a major threat the world is currently facing. Development of new antibiotics and the assessment of their toxicity represents an important challenge. Current methods to address antibiotic toxicity rely on measuring mitochondrial damage using ATP and/or membrane potential as a read-out. In this study, we propose an alternative read-out looking at changes in the lipidome on intact and unprocessed cells by MALDI mass spectrometry. As proof-of-principle, we evaluated the impact of known antibiotics (levofloxacin, ethambutol, and kanamycin) on the lipidome of HELA cells and mouse bone marrow-derived macrophages...
June 27, 2018: Chemical Research in Toxicology
Fabian Christoph Fischer, Cedric Abele, Steven T J Droge, Luise Henneberger, Maria König, Rita Schlichting, Stefan Scholz, Beate I Escher
Cellular uptake kinetics are key for understanding time-dependent chemical exposure in in vitro cell assays. Slow cellular uptake kinetics in relation to the total exposure time can considerably reduce the biologically effective dose. In this study, fluorescence microscopy combined with automated image analysis was applied for time-resolved quantification of cellular uptake of ten neutral, anionic, cationic, and zwitterionic fluorophoresin two reporter gene assays. The chemical fluorescence in the medium remained relatively constant during the 24-hourassay duration, emphasizing that the proteins and lipids in the fetal bovine serum (FBS) supplemented to the assay medium represent a large reservoir of reversibly bound chemicals with the potential to compensate for chemical depletion by cell uptake, growth, and sorption to well materials...
June 25, 2018: Chemical Research in Toxicology
Alastair Mak, Tiffany Elizabeth Cho, Jack Uetrecht
If idiosyncratic drug-induced liver injury (IDILI) is immune mediated, then it is logical that immune modulators may be able to affect liver injury caused by a drug. We have previously shown that modulating the immune system by impairing programmed cell death protein (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) signaling, both receptors involved in immune tolerance, was capable of producing an animal model of amodiaquine (AQ) IDILI with characteristics very similar to IDILI in humans. Other immune modulators may also increase liver injury caused by drugs that cause IDILI in humans...
June 25, 2018: Chemical Research in Toxicology
Preetleen Kathuria, Purshotam Sharma, Richard A Manderville, Stacey D Wetmore
Exposure to ochratoxin A (OTA) is associated with chronic renal diseases and carcinogenesis. The deleterious effects of OTA have been linked to its covalent binding at C8 position of guanine (G) to form DNA adduct (OT-G), which causes various mutations. To contribute towards understanding the complex mutagenic profile of OTA, the present work uses a robust computational approach to characterize post-replication DNA structures containing OT-G mismatched with canonical nucleobases. Our MD simulations provide insight into the effects of the opposing base, adduct ionization state and flanking base on duplex structural features for the competing (major groove (B-type), wedge (W) and stacked (S)) conformers...
June 20, 2018: Chemical Research in Toxicology
Kalpana Javvaji, Gousia Begum, Shruti S Deshpande, Rohit Kumar Rana, Sunil Misra
Calcium carbonate (CaCO3) based materials as feasible pH sensitive drug carriers which can actively dissolve in acidic microenvironment of cancer cells, are finding increasing importance. This has drawn our interest in the development of a bio-inspired polypeptide- mediated method to design calcium carbonate microspheres loaded with tetracycline (CaCO3-TC) with an aim to explore its safe application in cancer therapeutics. Its therapeutic application in cancer patients essentially demands its safety information on the normal cells...
June 20, 2018: Chemical Research in Toxicology
Shigehisa Uchiyama, Mayumi Noguchi, Nao Takagi, Hideki Hayashida, Yohei Inaba, Hironao Ogura, Naoki Kunugita
As a new form of cigarettes, heated tobacco products (HTPs) have been rapidly distributed worldwide. In this study, an improved method for analyzing gaseous and particulate compounds generated from HTPs is described. Smoke is collected using a GF-CX572 sorbent cartridge with 300 mg of carbon molecular sieves, that is, Carboxen 572 (CX572), and a 9 mm glass-fiber filter (GF). After collection, the CX572 particles from the cartridge are transferred along with the GF and deposited into a vial containing two phases of carbon disulfide and methanol...
June 19, 2018: Chemical Research in Toxicology
Gracia M Amaya, Rebecca Durandis, David S Bourgeois, James A Perkins, Arsany A Abouda, Kahari J Wines, Mohamed Mohamud, Samuel A Starks, R Nathan Daniels, Klarissa D Jackson
Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors...
June 18, 2018: Chemical Research in Toxicology
Tara Nguyen, Gerard E Li, Hui Chen, Charles G Cranfield, Kristine C McGrath, Catherine A Gorrie
Electronic cigarette (e-cigarette) use is on the rise worldwide and is particularly attractive to young people and as a smoking substitute by pregnant woman. There is a perception in pregnant women and women of child-bearing age that the use of e-cigarettes (vaping) is safer than smoking tobacco cigarettes during pregnancy. However, there is little evidence to support this perception. Here, we examined the offspring from mouse dams that had been exposed during and after pregnancy to ambient air (sham) ( n = 8), e-cigarette aerosols with nicotine ( n = 8), or e-cigarette aerosols without nicotine ( n = 8)...
June 15, 2018: Chemical Research in Toxicology
Monika Schmidt, Veronika Hrabcova, Daniel Jun, Kamil Kuca, Kamil Musilek
Mosquito-borne diseases (including malaria) belong among the leading causes of death in humans. Vector control is a crucial part of the global strategy for management of mosquito-associated diseases, when insecticide use is the most important component in this effort. However, drug and insecticide resistance threaten the successes made with existing methods. Reduction or elimination of malaria is not possible without effective mosquito control. This article reviews current strategies of intervention in vector control to decrease transmission of disease and covers current relevant knowledge in molecular biology, biochemistry, and medicinal chemistry...
June 15, 2018: Chemical Research in Toxicology
Tasaduq Hussain Wani, Sreeraj Surendran, Anal Jana, Anindita Chakrabarty, Goutam Chowdhury
Sepantronium bromide (YM155) is a small molecule antitumor agent currently in phase II clinical trials. Although developed as survivin suppressor, YM155's primary mode of action has recently been found to be DNA damage. However, the mechanism of DNA damage by YM155 is still unknown. Knowing the mechanism of action of an anticancer drug is necessary to formulate a rational drug combination and select a cancer type for achieving maximum clinical efficacy. Using cell-based assays we showed that YM155 cause extensive DNA cleavage and reactive oxygen species generation...
June 13, 2018: Chemical Research in Toxicology
Junjie Zhu, Pengcheng Wang, Amina Ibrahim Shehu, Jie Lu, Huichang Bi, Xiaochao Ma
Idelalisib (ILB) is a selective phosphatidylinositol-3-kinase delta inhibitor approved for the treatment of hematological malignancies. However, ILB frequently causes hepatotoxicity and the exact mechanism remains unclear. The current study profiled the metabolites of ILB in mouse liver, urine and feces. The major metabolites found in the liver were oxidized metabolite GS-563117 (M1) and ILB-glutathione (GSH) adduct (M2). These metabolic pathways were confirmed by analysis of urine and feces from mice treated with ILB...
June 13, 2018: Chemical Research in Toxicology
Qingsu Xia, Xiaobo He, Liang Ma, Shoujun Chen, Peter P Fu
Pyrrolizidine alkaloids (PAs) and their N-oxide derivatives are hepatotoxic, genotoxic, and carcinogenic phytochemicals. PAs induce liver tumors through a general genotoxic mechanism mediated by a set of four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5 H-pyrrolizine (DHP)-derived DNA adducts. To date, the primary pyrrolic metabolites dehydro-PAs, their hydrolyzed metabolite DHP, and two secondary pyrrolic metabolites 7-glutathione-DHP (7-GS-DHP) and 7-cysteine-DHP are the known metabolites that can generate these DHP-DNA adducts in vivo and/or in PA-treated cells...
June 13, 2018: Chemical Research in Toxicology
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