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Chemical Research in Toxicology

Dong-Sheng Zhao, Li-Long Jiang, Ya-Xi Fan, Ling-Li Wang, Zhuo-Qing Li, Wei Shi, Ping Li, Hui-Jun Li
The use of herbal medicines continues to expand globally, meanwhile, herb-associated hepatotoxicity is becoming a safety issue. Dioscorea bulbifera rhizome (DBR), a traditionally used medicinal plant in China, is reported to induce hepatotoxicity. However, the precise molecular mechanism involved has not been comprehensively explored. The objectives of the present study were to profile entire endogenous metabolites in a biological system and provide additional insight into the molecular mechanism of the hepatotoxicity induced by DBR using a multi-sample integrated metabolomics strategy...
September 13, 2017: Chemical Research in Toxicology
Jarno E J Wolters, Simone G J van Breda, Florian Caiment, Sandra M Claessen, Theo M C M de Kok, Jos C S Kleinjans
Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs in the world. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunction. The aim of this study is to further investigate VPA-induced mechanisms of steatosis by analyzing changes in patterns of methylation in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, primary human hepatocytes (PHHs) were exposed to an incubation concentration of VPA that was shown to cause steatosis without inducing overt cytotoxicity...
September 13, 2017: Chemical Research in Toxicology
Vimal Veeriah, Pavitra Kumar, Lakshmikirupa Sundaresan, Zeenath Mafitha, Ravi Gupta, Uttara Saran, Jeganathan Manivannan, Suvro Chatterjee
Since the conception of thalidomide as a teratogen approximately 30 hypotheses have been put forward to explain the developmental toxicity of the molecule. However, no systems biology approach has been taken to understand the phenomena yet. The proposed work was aimed to explore the mechanism of thalidomide toxicity in developing chick embryo in the context of transcriptomics by using genome wide RNA sequencing data. In this study, we challenged the developing embryo at the stage of blood island formations (HH8) which is the most vulnerable stage for thalidomide-induced deformities...
September 11, 2017: Chemical Research in Toxicology
Alicia J Dafferner, Lawrence M Schopfer, Gaoping Xiao, John R Cashman, Udaya Yerramalla, Rudolph C Johnson, Thomas A Blake, Oksana Lockridge
Nerve agents and organophosphorus pesticides make a covalent bond with the active site serine of acetylcholinesterase (AChE), resulting in inhibition of AChE activity and toxic symptoms. AChE in red blood cells (RBC) serves as a surrogate for AChE in the nervous system. Mass spectrometry analysis of adducts on RBC AChE could provide evidence of exposure. Our goal was to develop a method of immunopurifying human RBC AChE in quantities adequate for detecting exposure by mass spectrometry. For this purpose we immobilized 3 commercially available anti-human acetylcholinesterase monoclonals (AE-1, AE-2, and HR2) plus 3 new monoclonals...
September 11, 2017: Chemical Research in Toxicology
Jinhua Li, Madlen Bauer, Birget Moe, Elaine M Leslie, Xing-Fang Li
Halobenzoquinones (HBQs) are frequently detected disinfection byproducts (DBPs) in treated water. Recent studies have demonstrated that HBQs are highly cytotoxic and capable of inducing the generation of reactive oxygen species (ROS) and depleting cellular glutathione (GSH). Multidrug resistance proteins (MRPs/ABCCs) are known to play a critical role in the elimination of numerous drugs, carcinogens, toxicants, and their conjugated metabolites. In general, little is known about the roles of transporters in DBP toxicity...
September 8, 2017: Chemical Research in Toxicology
Liuxi Chen, James D Smith, Jaromir Mikl, Ryan Fryer, Frank Pack, Brad J Williams, Jonathan Phillips, Vladimir Papov
Drug-induced kidney injury (DIKI) is a common toxicity observed in pharmaceutical development. We demonstrate the use of label-free liquid chromatography - mass spectrometry (LC-MS) and multiplex liquid chromatography-single reaction monitoring (LC-SRM) as practical extensions of standard immunoassay based safety biomarker assessments for identification of new toxicity marker candidates and for improved mechanistic understanding. Two different anti-cancer drugs doxorubicin (DOX) and cisplatin (cis-diamminedichloridoplatinum, CDDP) were chosen as the toxicants due to their different modes of nephrotoxicity...
September 8, 2017: Chemical Research in Toxicology
Valérie Forest, Jean-Michel Vergnon, Jérémie Pourchez
Although necessary, in vitro and in vivo studies are not fully successful at predicting nanomaterials toxicity. We propose to associate such assays to the biological monitoring of nanoparticles in clinical samples to get more relevant data on the chemical and physical nature and dose of nanoparticles found in humans. The concept is to establish the load of nanoparticles in biological samples of patients. Then, by comparing samples from different patient groups, nanoparticles of interest could be identified and a potential link between a given nanoparticle type and toxicity could be suggested...
September 8, 2017: Chemical Research in Toxicology
Michael A Trakselis, Matthew T Cranford, Aurea M Chu
The ability for DNA polymerases (Pols) to overcome a variety of obstacles in its path to maintain genomic stability during replication is a complex endeavor. It requires the coordination of multiple Pols with differing specificities through molecular control and access to the replisome. Although a number of contacts directly between Pols and to accessory proteins have been identified forming the basis of a variety of holoenzyme (HE) complexes, the dynamics of Pol active site substitutions remain uncharacterized...
September 7, 2017: Chemical Research in Toxicology
Lok Ming Tam, Ji Jiang, Pengcheng Wang, Lin Li, Weili Miao, Xuejiao Dong, Yinsheng Wang
Arsenic is a ubiquitous environmental contaminant with widespread public health concern. Epidemiological studies have revealed that chronic human exposure to arsenic in drinking water is associated with the prevalence of skin, lung, and bladder cancers. Aberrant histone modifications (e.g., methylation, acetylation, and ubiquitination) were previously found to be accompanied by arsenic exposure; thus, perturbation of epigenetic pathways is thought to contribute to arsenic carcinogenesis. Arsenite is known to interact with zinc finger motifs of proteins, and zinc finger motif is present in and indispensable for the enzymatic activities of crucial histone-modifying enzymes especially the MYST family of histone acetyltransferases (e...
September 7, 2017: Chemical Research in Toxicology
Hideshi Ihara, Shingo Kasamatsu, Atsushi Kitamura, Akira Nishimura, Hiroyasu Tsutsuki, Tomoaki Ida, Kento Ishizaki, Takashi Toyama, Eiko Yoshida, Hisyam Abdul Hamid, Minkyung Jung, Tetsuro Matsunaga, Shigemoto Fujii, Tomohiro Sawa, Motohiro Nishida, Yoshito Kumagai, Takaaki Akaike
Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP...
September 7, 2017: Chemical Research in Toxicology
Alice R Walker, G Andres Cisneros
Genetic information is vital in the cell cycle of DNA--based organisms. DNA Polymerases (DNA Pols) are crucial players in transactions dealing with these processes. Therefore, the detailed understanding of the structure, function, and mechanism of these proteins has been the focus of significant effort. Computational simulations have been applied to investigate various facets of DNA polymerase structure and function. These simulations have provided significant insights over the years. This perspective presents the results of various computational studies that have been employed to research different aspects of DNA polymerases including detailed reaction mechanism investigation, mutagenicity of different metal cations, possible factors for fidelity synthesis, and discovery/functional characterization of cancer--related mutations on DNA polymerases...
September 6, 2017: Chemical Research in Toxicology
Likui Zhang
The bacteriophage T4 DNA polymerase (pol) and the closely related RB69 DNA pol have been developed into model enzymes to study family B DNA pols. While all family B DNA pols have similar structures and share conserved protein motifs, the molecular mechanism underlying natural drug resistance of non-herpes family B DNA pols and drug sensitivity of herpes DNA pols remains unknown. In the present study, we constructed T4 phages containing G466S, Y460F, G466S/Y460F, P469S and V475W mutations in DNA pol. These amino acid substitutions replace the residues in drug-resistant T4 DNA pol with residues found in drug-sensitive herpes family DNA pols...
September 5, 2017: Chemical Research in Toxicology
Meichen Wang, Cody R Maki, Youjun Deng, Yanan Tian, Timothy D Phillips
Previously, a calcium montmorillonite clay (NovaSil) included in the diet of animals has been shown to bind aflatoxin B1 (AfB1) and reduce the symptoms of aflatoxicosis. To investigate and improve the capacity and efficacy of clay-based materials as aflatoxin sorbents, we developed and tested calcium and sodium montmorillonite clays amended with nutrients including l-carnitine and choline. Also, we determined the sorption of AfB1 by isothermal analysis and tested the ability of these amended sorbents to protect adult hydra from AfB1 toxicity...
September 5, 2017: Chemical Research in Toxicology
Matthew A Schaich, Mallory R Smith, Ashley S Cloud, Sean M Holloran, Bret D Freudenthal
Members of the nucleoside analogue class of cancer therapeutics compete with canonical nucleotides to disrupt numerous cellular processes, including nucleotide homeostasis, DNA and RNA synthesis, and nucleotide metabolism. Nucleoside analogues are triphosphorylated and subsequently inserted into genomic DNA, contributing to the efficacy of therapeutic nucleosides in multiple ways. In some cases, the altered base acts as a mutagen, altering the DNA sequence to promote cellular death; in others, insertion of the altered nucleotide triggers DNA repair pathways, which produce lethal levels of cytotoxic intermediates such as single and double stranded DNA breaks...
September 1, 2017: Chemical Research in Toxicology
Stephanus Johannes Lourens Linde, Anja Franken, Johannes Lodewykus du Plessis
Platinum Group Metals (PGMs) is a group of metals that include platinum, palladium, rhodium, ruthenium, iridium and osmium. Occupational respiratory exposure to platinum has been reported since 1945 but studies investigating occupational exposure to palladium, rhodium, ruthenium, iridium and osmium are scarce. This review provides a summation of the information available on the respiratory exposure to PGMs in various industrial settings, methods used to assess exposure and the possible adverse health effects resulting from occupational exposure to PGMs...
August 31, 2017: Chemical Research in Toxicology
Katie A Wilson, Stacey D Wetmore
Although translesion synthesis (TLS) polymerases play key roles in replicating DNA that contains nucleobase addition products (adducts), there are many unknowns about their function. The present work gains indispensable structural insights from molecular dynamics simulations on the replication of O6-benzyl-guanine (Bz-dG) prior to bond formation during dCTP insertion opposite the adduct by Dpo4. When combined with previous X-ray crystal structures of the Bz-dG extension complex, molecular details are now available for each stage during a single TLS replication cycle for this carcinogenic lesion...
August 31, 2017: Chemical Research in Toxicology
Thomas Nauser, Janusz M Gebicki
The principal initial biological targets of free radicals formed under conditions of oxidative stress are the proteins. The most common products of the interaction are carbon-centered alkyl radicals which react rapidly with oxygen to form peroxyl radicals and hydroperoxides. All these species are reactive, capable of propagating the free radical damage to enzymes, nucleic acids, lipids, and endogenous antioxidants, leading finally to the pathologies associated with oxidative stress. The best chance of preventing this chain of damage is in early repair of the protein radicals by antioxidants...
August 29, 2017: Chemical Research in Toxicology
Maroof K Zafar, Robert L Eoff
The genomic landscape of cancer is one marred by instability, but the mechanisms that underlie these alterations are multi-faceted and remain a topic of intense research. Cellular responses to DNA damage and/or replication stress can affect genome stability in tumors and influence the response of patients to therapy. In addition to direct repair, DNA damage tolerance (DDT) is an element of genomic maintenance programs that contributes to the etiology of several types of cancer. DDT mechanisms primarily act to resolve replication stress, and this can influence the effectiveness of genotoxic drugs...
August 25, 2017: Chemical Research in Toxicology
Barbara van Loon, Ulrich Hubscher, Giovanni Maga
In human cells, only four DNA polymerases (pols) are necessary and sufficient for the duplication of the genetic information. However, more than a dozen DNA pols are required to maintain its integrity. Such a high degree of specialization, makes DNA repair pols able to cope with specific lesions or repair pathways. On the other hand, the same DNA pols can have partially overlapping roles, which could result in possible conflicts of functions, if the DNA pols are not properly regulated. DNA pol λ is a typical example of such an enzyme...
August 25, 2017: Chemical Research in Toxicology
Jinming Wu, Jie Zhao, Zhen Yang, Hailing Li, Zhonghong Gao
The deposition of human islet amyloid polypeptide (hIAPP) within β-cells is implicated in the etiology of type 2 diabetes mellitus (T2Dm). It was reported that heme could bind to hIAPP. We speculate that binding may affect the aggregation of hIAPP. In this study, UV-vis spectroscopy was used to detect the interaction pattern between the heme and hIAPP. ThT and Bis-ANS fluorescence assay, circular dichroism spectroscopy, gel electrophoresis assay, and transmission electron microscopy were employed to study the effect of heme on the aggregation of hIAPP...
August 23, 2017: Chemical Research in Toxicology
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