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Chemical Research in Toxicology

James J Galligan, Lawrence J Marnett
Bioactive electrophiles generated from the oxidation of endogenous and exogenous compounds are a contributing factor in numerous disease states. Their toxicity is largely attributed to the covalent modification of cellular nucleophiles, including protein and DNA. With regard to protein modification, the side-chains of Cys, His, Lys, and Arg residues are critical targets. This results in the generation of undesired protein post-translational modifications (PTMs), that can trigger dire cellular consequences. Notably, histones are Lys- and Arg-rich proteins, providing a fertile source for adduction by both exogenous and endogenous electrophiles...
December 8, 2016: Chemical Research in Toxicology
Ruifeng Liu, Xueping Yu, Anders Wallqvist
Chemical toxicity is conventionally evaluated in animal models. However, animal models are resource intensive; moreover, they face ethical and scientific challenges because the outcomes obtained by animal testing may not correlate with human responses. To develop an alternative method for assessing chemical toxicity, we investigated the feasibility of using chemical-induced genome-wide expression changes in cultured human cells to predict the potential of a chemical to cause specific organ injuries in humans...
November 4, 2016: Chemical Research in Toxicology
Wenyan Xu, Daniel Kool, Derek K O'Flaherty, Ashley M Keating, Lauralicia Sacre, Martin Egli, Anne Noronha, Christopher J Wilds, Linlin Zhao
DNA interstrand cross-links (ICLs) are cytotoxic DNA lesions derived from reactions of DNA with a number of anti-cancer reagents as well as endogenous bifunctional electrophiles. Deciphering the DNA repair mechanisms of ICLs is important for understanding the toxicity of DNA cross-linking agents and for developing effective chemotherapies. Previous research has focused on ICLs cross-linked with the N7 and N2 atoms of guanine as well as those formed at the N6 atom of adenine; however, little is known about the mutagenicity of O(6)-dG-derived ICLs...
November 4, 2016: Chemical Research in Toxicology
Trevor M Penning
Human Aldo-Keto Reductases are NAD(P)H dependent oxidoreductases that convert aldehydes and ketones to primary and secondary alcohols for subsequent conjugation reactions and can be referred to as "phase 1" enzymes. Among all the human genes regulated by the Keap1/Nrf2 pathway they are consistently the most overexpressed in response to Nrf2 activators. While these enzymes play clear cytoprotective roles and deal effectively with carbonyl stress, their up-regulation by the Keap1/Nrf2 pathway also has a potential dark-side, which can lead to chemotherapeutic drug resistance, and the metabolic activation of lung carcinogens (e...
November 3, 2016: Chemical Research in Toxicology
Junhong Guo, Mikhail D Linetsky, Annabelle O Yu, Liang Zhang, Scott J Howell, Heather J Folkwein, Hua Wang, Robert G Salomon
Oxidative stress and angiogenesis have been implicated not only in normal phenomena such as tissue healing and remodeling but also in many pathological processes. However, the relationships between oxidative stress and angiogenesis still remain unclear, although oxidative stress has been convincingly demonstrated to influence the progression of angiogenesis under physiological and pathological conditions. The retina is particularly susceptible to oxidative stress owing to its intensive oxygenation and high abundance of polyunsaturated fatty acyls...
November 3, 2016: Chemical Research in Toxicology
Jiaming Chen, Ying Peng, Jiang Zheng
Saracatinib is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anticancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1-M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib...
November 3, 2016: Chemical Research in Toxicology
Jingjing Liu, K K Jason Chan, Wan Chan
Chemical modifications of proteins have been well-documented to play important roles in normal cell physiology such as cell signaling and protein functions. They have also been demonstrated to be one of the milestones in the pathophysiology of many human diseases such as cancer, age-related pathology, and neurodegenerative disorders. Here we report the initial identification of a novel protein modification, cysteine thiazolidination, through reaction with endogenous and exogenous formaldehyde with cysteine residues in proteins...
November 2, 2016: Chemical Research in Toxicology
Monday O Ogese, Shaheda Ahmed, Ana Alfirevic, Catherine J Betts, Anne Dickinson, Lee Faulkner, Neil S French, Andrew Gibson, Gideon M Hirschfield, Michael Ernst Kammüller, Xiaoli Meng, Stefan F Martin, Philippe Musette, Alan Norris, Munir Pirmohamed, Brian Kevin Park, Anthony Wayne Purcell, Colin F Spraggs, Jessica Whritenour, Dean John Naisbitt
The workshop on "New approaches to investigate drug-induced hypersensitivity" was held on June 5 2014 at the Foresight centre, University of Liverpool. The aims of the workshop were to (1) discuss our current understanding of the genetic, clinical and chemical basis of small molecule drug hypersensitivity (2) highlight the current status of assays that might be developed to predict potential drug immunogenicity, (3) identify the limitations, knowledge gaps and challenges that limit the use of these assays and utilise the knowledge gained from the workshop to develop a pathway to establish new and improved assays that better predict drug-induced hypersensitivity reactions during the early stages of drug development...
November 2, 2016: Chemical Research in Toxicology
Amit S Kalgutkar
Soft electrophiles (e.g., epoxides, quinones, quinone-imines, quinone-methides, etc.) generated via the oxidative bioactivation of phenyl, phenolic, amino- and alkylphenolic substituents can be trapped with nucleophiles of comparable softness (e.g., glutathione or cysteine) in reactive metabolite screens. In contrast, hard nucleophiles such as cyanide and amines are frequently utilized to trap hard electrophiles (e.g., iminiums and aldehydes) that result from the oxidative bioactivation of cyclic (or acylic) amines and primary alcohols...
November 2, 2016: Chemical Research in Toxicology
Philip C Burcham
Acrolein is a highly toxic electrophile that participates in many diseases, yet efforts to delineate its precise mechanistic contributions to specific conditions are complicated by its wide distribution within human environments. This Perspective develops the proposal that due to its mixed status as environmental pollutant, metabolic by-product, and endotoxicant which forms via ubiquitous pathophysiological processes, many diseases likely involve acrolein released from multiple sources. Although the category boundaries are indistinct, at least four identifiable exposure scenarios are identifiable...
November 2, 2016: Chemical Research in Toxicology
David H Petering
Understanding the molecular basis of inorganic chemical toxicity has lagged behind the proliferation of detailed mechanisms that explain the biochemical toxicology of many organic xenobiotics. In this perspective, general barriers to explicating the bioinorganic chemistry of toxic metal are considered, followed by a detailed examination of these issues in relation to the toxicology of Cd(2+). The hypothesis is evaluated that Cd(2+) damages cells by replacing Zn(2+) in key Zn-proteins. Emerging methodology to assess the speciation of metals among cell proteins is described...
November 2, 2016: Chemical Research in Toxicology
Dinesh Kumar Barupal, Kent E Pinkerton, Carol Hood, Tobias Kind, Oliver Fiehn
Human exposure to environmental tobacco smoke (ETS) is associated with an increased incidence of pulmonary and cardiovascular disease and possibly lung cancer. Metabolomics can reveal changes in metabolic networks in organisms under different physio-pathological conditions. Our objective was to identify spatial and temporal metabolic alterations with acute and repeated subchronic ETS exposure to understand mechanisms by which ETS exposure may cause adverse physiological and structural changes in the pulmonary and cardiovascular systems...
October 28, 2016: Chemical Research in Toxicology
Robert G Nichols, Nicole E Hume, Philip B Smith, Jeffrey M Peters, Andrew D Patterson
The drug metabolism field has long recognized the beneficial and sometimes deleterious influence of microbiota in the absorption, distribution, metabolism, and excretion of drugs. Early pioneering work with the sulfanilamide precursor prontosil pointed toward the necessity not only to better understand the metabolic capabilities of the microbiota but also, importantly, to identify the specific microbiota involved in the generation and metabolism of drugs. However, technological limitations important for cataloging the microbiota community as well as for understanding and/or predicting their metabolic capabilities hindered progress...
October 26, 2016: Chemical Research in Toxicology
Tiffany Elizabeth Cho, Jack Uetrecht
Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells...
October 24, 2016: Chemical Research in Toxicology
Jochem Louisse, Karsten Beekmann, Ivonne Magdalena Catharina Maria Rietjens
The development of reliable non-animal based testing strategies, such as in vitro bioassays, is the holy grail in current human safety testing of chemicals. However, the use of in vitro toxicity data in risk assessment is not straightforward. One of the main issues is that concentration-response curves from in vitro models need to be converted to in vivo dose-response curves. These dose-response curves are needed in toxicological risk assessment to obtain a point of departure to determine safe exposure levels for humans...
October 21, 2016: Chemical Research in Toxicology
Richard A Manderville, Stacey D Wetmore
The formation of DNA adducts by the attack of intermediates derived from toxic substances at the C8 position of 2-deoxyguanosine (dG) is a common damaging event. Although the majority of studies on C8-dG adducts have focused on lesions containing a C8-N-C tether between the bulky moiety and the nucleobase, the formation of O-linked lesions with a similar tether topology and C-linked adducts involving direct C8-C connectivity have also been uncovered. Several studies have been done to try to better understand the structural impact and mutagenicity of O-linked and C-linked aryl C8-dG adducts, including lesions arising from unsubstituted and chloro substituted phenols, and the food mutagen ochratoxin A (OTA)...
October 21, 2016: Chemical Research in Toxicology
Mikael Persson, Jorrit J Hornberg
High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile...
October 21, 2016: Chemical Research in Toxicology
Ashis K Basu, Paritosh Pande, Arindam Bose
With the discovery of translesion synthesis DNA polymerases, great strides have been made in the last two decades in understanding the mode of replication of various DNA lesions in prokaryotes and eukaryotes. A database search indicated that approximately 2000 articles on this topic have been published in this period. This includes research involving genetic and structural studies as well as in vitro experiments using purified DNA polymerases and accessory proteins. It is a daunting task to comprehend this exciting and rapidly emerging area of research...
October 19, 2016: Chemical Research in Toxicology
Robert G Salomon
Our research on the roles of lipid oxidation in human disease is guided by chemical intuition. For example, we postulated that 2-(ω-carboxyethyl)pyrrole (CEP) derivatives of primary amines would be produced through covalent adduction of a γ-hydroxyalkenal generated, in turn, through oxidative fragmentation of docosahexaenoates. Our studies confirmed the natural occurrence of this chemistry, and the biological activities of these natural products and their extensive involvements in human physiology (wound healing) and pathology (age-related macular degeneration, autism, atherosclerosis, sickle cell disease and tumor growth) continue to emerge...
October 17, 2016: Chemical Research in Toxicology
Hiroshi Yamazaki
Research over the past 30 years has elucidated the roles of polymorphic human liver cytochrome P450 (P450) enzymes associated with toxicological and/or pharmacological actions. Thalidomide exerts its various pharmacological and toxic actions in primates through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by autoinduced human P450 enzymes. To overcome species-differences between rodents, currently, nonhuman primates and/or mouse models with transplanted human hepatocytes are used...
October 17, 2016: Chemical Research in Toxicology
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