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Chemical Research in Toxicology

Yanli Zhang, Hui Huang, Biao Gong, Leizhen Duan, Long Sun, Tongkun He, Xuemin Cheng, Zhiyuan Li, Liuxin Cui, Yue Ba
Although increasing evidence suggests that estrogen receptor α (ESRα) genetic variation could modify bone damage caused by environmental fluoride exposure, little is known about epigenetic mechanisms in relation to bone changes. A case-control study was conducted among farmers aged 18-55 years in Henan Province, China. X-ray was used to detect bone changes. Methylation status was determined by methylation-specific PCR. Genotypes were identified by Taqman probe and real-time PCR. In this study, we found that methylation status in the promoter region of the ESRα gene was lower in bone change cases than that in controls, which was only observed in male farmers after stratification by gender...
May 23, 2017: Chemical Research in Toxicology
Hongbin Yang, Jie Li, Zengrui Wu, Weihua Li, Guixia Liu, Yun Tang
Identification of structural alerts for toxicity is useful in drug discovery and other fields such as environmental protection. With structural alerts, researchers can quickly identify potential toxic compounds and learn how to modify them. Hence, it is important to determine structural alerts from a large number of compounds quickly and accurately. There are already many methods reported for identification of structural alerts. However, how to evaluate those methods is a problem. In this paper, we tried to evaluate four of the methods for monosubstructure identification with three indices including accuracy rate, coverage rate, and information gain to compare their advantages and disadvantages...
May 23, 2017: Chemical Research in Toxicology
Mandeep Singh Bakshi
Nanotoxicity of nanomaterials is an important issue in view of their potential applications in systemic circulation and wound healing dressing. This account specifically deals with several characteristic features of different nanomaterials which induce hemolysis and how to make them hemocompatible. The shape, size, and surface functionalities of naked metallic as well as nonmetallic nanoparticles surfaces are responsible for the hemolysis. An appropriate coating of biocompatible molecules dramatically reduces hemolysis and promotes their ability as safe drug delivery vehicles...
May 23, 2017: Chemical Research in Toxicology
Ryuji Kato, Jack Uetrecht
There is increasing evidence that most idiosyncratic drug-induced liver injury (IDILI) is immune mediated, and in most cases reactive metabolites appear to be responsible for induction of this immune response. Reactive metabolites can cause cell damage with the release of damage-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Presumably the reason that the liver is a common target of idiosyncratic drug reactions is because it is the major site of drug metabolism and reactive metabolite formation...
May 19, 2017: Chemical Research in Toxicology
Michael D Aleo, Falgun Shah, Kan He, Paul D Bonin, A David Rodrigues
No abstract text is available yet for this article.
May 18, 2017: Chemical Research in Toxicology
Blake R Rushing, Mustafa I Selim
Aflatoxin B2a has been shown to bind to proteins through a dialdehyde intermediate under physiological conditions. The proposed structure of this adduct has been published showing a Schiff base interaction, but adequate verification using structural elucidation instrumental techniques has not been performed. In this work, we synthesized the aflatoxin B2a amino acid adduct under alkaline conditions and the formation of a new product was determined using high performance liquid chromatography-time of flight mass spectrometry...
May 17, 2017: Chemical Research in Toxicology
Tingting Cai, Medjda Bellamri, Xun Ming, Woon-Puay Koh, Mimi C Yu, Robert J Turesky
Aromatic amines covalently bound to hemoglobin (Hb) as sulfinamide adducts at the cysteine 93 residue of the Hb β chain have served as biomarkers to assess exposure to this class of human carcinogens for the past 30 years. In this study, we report that 2-amino-9H-pyrido[2,3-b]indole (AαC), an abundant carcinogenic heterocyclic aromatic amine formed in tobacco smoke and charred cooked meats, also reacts with Hb to form a sulfinamide adduct. A novel nanoflow liquid chromatography/ion trap multistage mass spectrometry (nanoLC-IT/MS3) method was established to assess exposure to AαC and the tobacco-associated bladder carcinogen 4-aminobiphenyl (4-ABP) through their Hb sulfinamide adducts...
May 11, 2017: Chemical Research in Toxicology
David W Roberts, Terry Wayne Schultz, Anne Marie Api
The general chemistry principles underlying skin sensitization for Schiff base (SB) electrophiles may be used to develop a quantitative mechanistic model (QMM), based on reactivity supplemented with a hydrophobicity parameter for some but not all structures within the SB reaction domain. For aliphatic Schiff base electrophiles, the log of the no observed effect level (NOEL) values (pNOEL) from the human repeated insult patch test (HRIPT) can be calculated by the reactivity parameter summation of sigma star values ( Σσ*) and a hydrophobicity parameter (logP)...
May 11, 2017: Chemical Research in Toxicology
Suzanne J Admiraal, Patrick J O'Brien
Nicking of the DNA strand immediately upstream of an internal abasic (AP) site produces 5'-terminal abasic (dRp) DNA. Both the intact and the nicked abasic species are reactive intermediates along the DNA base excision repair (BER) pathway and can be derailed by side reactions. Aberrant accumulation of the 5'-terminal abasic intermediate has been proposed to lead to cell death, so we explored its reactivity and compared it to the reactivity of the better-characterized internal abasic intermediate. We find that the 5'-terminal abasic group cross-links with the exocyclic amine of a nucleotide on the opposing strand to form an interstrand DNA-DNA cross-link (ICL)...
May 9, 2017: Chemical Research in Toxicology
Romina Castañeda-Arriaga, Annia Galano
Several chemical routes related to the toxicity of paracetamol (APAP, also known as acetaminophen), its analog N-acetyl-m-aminophenol (AMAP), and their deacetylated derivatives, were investigated using the Density Functional Theory. It was found that AMAP is more resilient to chemical oxidation than APAP. The chemical degradation of AMAP into radical intermediates is predicted to be significant only when it is induced by strong oxidants. This might explain the apparent contradictions among experimental evidences regarding the AMAP toxicity...
May 5, 2017: Chemical Research in Toxicology
Michael D Aleo, Falgun Shah, Kan He, Paul D Bonin, A David Rodrigues
The role of bile salt export protein (BSEP) inhibition in drug-induced liver injury (DILI) has been investigated widely, while inhibition of the canalicular multidrug resistant protein 3 (MDR3) has received less attention. This transporter plays a pivotal role in secretion of phospholipids into bile and functions coordinately with BSEP to mediate the formation of bile acid-containing biliary micelles. Therefore, inhibition of MDR3 in human hepatocytes was examined across 125 drugs (70 of Most-DILI-concern and 55 of No-DILI-concern)...
May 4, 2017: Chemical Research in Toxicology
Fabricio Luís Lovato, João Batista Teixeira da Rocha, Cristiane Lenz Dalla Corte
Methylmercury (MeHg) is a ubiquitous and persistent environmental pollutant that induces serious neurotoxic effects. Diphenyl diselenide [(PhSe)2], an organoseleno compound, exerts protective effects against MeHg toxicity, although the complete mechanism remains unclear. The aim of this study was to investigate the mechanisms involved in the protective effect of (PhSe)2 on the toxicity induced by MeHg using wild-type Saccharomyces cerevisiae and mutants with defects in enzymes and proteins of the antioxidant defense system (yap1Δ, ybp1Δ, ctt1Δ, cat1Δ, sod1Δ, sod2Δ, gsh1Δ, gsh2Δ, gtt1Δ, gtt2Δ, gtt3Δ, gpx1Δ, gpx2Δ, trx1Δ, trx2Δ, trx3Δ, and trr2Δ)...
May 4, 2017: Chemical Research in Toxicology
Hong Mu, Nicholas E Geacintov, Jung-Hyun Min, Yingkai Zhang, Suse Broyde
The xeroderma pigmentosum C protein complex (XPC) recognizes a variety of environmentally induced DNA lesions and is the key in initiating their repair by the nucleotide excision repair (NER) pathway. When bound to a lesion, XPC flips two nucleotide pairs that include the lesion out of the DNA duplex, producing a productively bound complex that can lead to successful lesion excision. Interestingly, the efficiencies of NER vary greatly among different lesions, influencing their toxicity and mutagenicity in cells...
May 1, 2017: Chemical Research in Toxicology
Tamalika Ash, Tanay Debnath, Avik Ghosh, Abhijit Kumar Das
The detoxication of DMMP (dimethyl methylphosphonate) mediated by molecular TiO2 has been investigated computationally using density functional theory (DFT). From our previous studies, it is evident that the unimolecular detoxication of OPCs (organophosphorus compounds) is kinetically unfeasible at room temperature due to the significantly high activation barrier. Thus, the aim of our work is to find out whether molecular TiO2 can make any significant impact on the kinetic feasibility of the detoxication processes or not...
April 27, 2017: Chemical Research in Toxicology
Gunnar Boysen
Glutathione (GSH) is the most abundant antioxidant and is believed to maintain redox potential in tissues, cells, and individual compartments. However, GSH concentrations in some tumor cells and tissues have been reported to be as high as 1-10 mM, a concentration that is up to 10,000-fold higher than that of reactive oxygen species. Critical quantitative evaluation of glutathione's proposed functions suggests that glutathione is an amino acid checkpoint. In this role, glutathione contributes to regulating cell proliferation and apoptosis, pending amino acid availability...
April 26, 2017: Chemical Research in Toxicology
Hanwen Du, Yingchun Cai, Hongbin Yang, Hongxiao Zhang, Yuhan Xue, Guixia Liu, Yun Tang, Weihua Li
Environmental chemicals may affect endocrine systems through multiple mechanisms, one of which is via effects on aromatase (also known as CYP19A1), an enzyme critical for maintaining the normal balance of estrogens and androgens in the body. Therefore, rapid and efficient identification of aromatase-related endocrine disrupting chemicals (EDCs) is important for toxicology and environment risk assessment. In this study, on the basis of the Tox21 10K compound library, in silico classification models for predicting aromatase binders/nonbinders were constructed by machine learning methods...
April 26, 2017: Chemical Research in Toxicology
M Ceccarelli, B Wagner, R Alvarez-Sánchez, G Cruciani, L Goracci
In vitro safety assessment in early drug discovery represents an important step to detect potential safety-related liabilities. It reduces late stage attrition and allows candidate optimization. In this study, we report on the use of the LogDBPL assay (a recently published assay for the determination of drug distribution coefficients between an aqueous phase and porcine brain polar lipids extract) for phospholipidosis (PLD) risk evaluation. The LogDBPL parameter was first compared to the effective permeability in the parallel artificial membrane permeability assay (PAMPA), previously reported as correlating with PLD risk...
April 25, 2017: Chemical Research in Toxicology
Fabian C Fischer, Luise Henneberger, Maria König, Kai Bittermann, Lukas Linden, Kai-Uwe Goss, Beate I Escher
High-throughput in vitro bioassays are becoming increasingly important in the risk characterization of anthropogenic chemicals. Large databases gather nominal effect concentrations (Cnom) for diverse modes of action. However, the biologically effective concentration can substantially deviate due to differences in chemical partitioning. In this study, we modeled freely dissolved (Cfree), cellular (Ccell), and membrane concentrations (Cmem) in the Tox21 GeneBLAzer bioassays for a set of neutral and ionogenic organic chemicals covering a large physicochemical space...
April 24, 2017: Chemical Research in Toxicology
A S Prakasha Gowda, Jacek Krzeminski, Shantu Amin, Zucai Suo, Thomas E Spratt
Benzo[a]pyrene, a potent human carcinogen, is metabolized in vivo to a diol epoxide that reacts with the N(2)-position of guanine to produce N(2)-BP-dG adducts. These adducts are mutagenic causing G to T transversions. These adducts block replicative polymerases but can be bypassed by the Y-family translesion synthesis polymerases. The mechanisms by which mutagenic bypass occurs is not well-known. We have evaluated base pairing structures using atomic substitution of the dNTP with two stereoisomers, 2'-deoxy-N-[(7R,8S,9R,10S)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine and 2'-deoxy-N-[(7S,8R,9S,10R)-7,8,9,10-tetrahydro-7,8,9-trihydroxybenzo[a]pyren-10-yl]guanosine...
April 19, 2017: Chemical Research in Toxicology
Henrik Carlsson, Jenny Aasa, Natalia Kotova, Daniel Vare, Pedro F M Sousa, Per Rydberg, Lilianne Abramsson-Zetterberg, Margareta Törnqvist
Electrophilic compounds/metabolites present in humans, originating from endogenous processes or exogenous exposure, pose a risk to health effects through their reactions with nucleophilic sites in proteins and DNA, forming adducts. Adductomic approaches are developed to screen for adducts to biomacromolecules in vivo by mass spectrometry (MS), with the aim to detect adducts corresponding to unknown exposures from electrophiles. In the present study, adductomic screening was performed using blood samples from healthy children about 12 years old (n = 51)...
April 18, 2017: Chemical Research in Toxicology
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