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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
Jone Corrales, Lauren A Kristofco, W Baylor Steele, Gavin N Saari, Jakub Kostal, Edward Spencer Williams, Margaret Mills, Evan P Gallagher, Terrance J Kavanagh, Nancy Simcox, Longzhu Q Shen, Fjodor Melnikov, Julie B Zimmerman, Adelina M Voutchkova-Kostal, Paul T Anastas, Bryan W Brooks
Sustainable molecular design of less hazardous chemicals presents a potentially transformative approach to protect public health and the environment. Relationships between molecular descriptors and toxicity thresholds previously identified the octanol-water distribution coefficient, log D, and the HOMO-LUMO energy gap, ∆E, as two useful properties in the identification of reduced aquatic toxicity. To determine whether these two property-based guidelines are applicable to sublethal oxidative stress (OS) responses, two common aquatic in vivo models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio), were employed to examine traditional biochemical biomarkers (lipid peroxidation, DNA damage, total glutathione) and antioxidant gene activation following exposure to eight structurally diverse industrial chemicals (bisphenol A, cumene hydroperoxide, dinoseb, hydroquinone, indene, perfluorooctanoic acid, R-(-)-carvone, tert-butyl hydroperoxide)...
October 17, 2016: Chemical Research in Toxicology
Chih-Kai Chao, S Kaleem Ahmed, John M Gerdes, Charles M Thompson
The organophosphate O-(2-fluoroethyl)-O-(p-nitrophenyl) methyphosphonate 1 is the first-in-class, fluorine-18 radiolabeled organophosphate inhibitor ([(18)F]1) of acetylcholinesterase (AChE). In rats, [(18)F]1 localizes in AChE rich regions of the brain and other tissues where it likely exists as the (CH3)((18)FCH2CH2O)P(O)-AChE adduct (ChE-1). Characterization of this adduct would define the inhibition mechanism and subsequent postinhibitory pathways and reactivation rates. To validate this adduct, the stability (hydrolysis) of 1 and ChE-1 reactivation rates were determined...
October 17, 2016: Chemical Research in Toxicology
Prakasha Gowda, Thomas E Spratt
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco carcinogen that forms mutagenic DNA adducts including O(6)-methyl-2'-deoxyguanosine (O(6)-Me-dG), O(6)-[4-(3-pyridyl)-4-oxobut-1-yl]-dG (O6-POB-dG), O(2)-methylthymidine (O(2)-Me-dT), and O(2)-POB-dT. We evaluated the ability of human DNA polymerase ν to bypass this damage to evaluate the structural constraints on substrates for pol ν and to evaluate if there is kinetic evidence suggesting the in vivo activity of pol ν on tobacco-induced DNA damage...
October 14, 2016: Chemical Research in Toxicology
Yakov M Koen, Ke Liu, Heather Shinogle, Todd D Williams, Robert P Hanzlik
The hepatotoxicity of acetaminophen (APAP) is generally attributed to the formation of a reactive quinoneimine metabolite (NAPQI) that depletes glutathione and covalently binds to hepatocellular proteins. To explore the importance of the N-acyl group in APAP metabolism and toxicity, we synthesized 12 acyl side chain homologues of acetaminophen (APAP) and its 3'-regioisomer (AMAP), including the respective N-(4-pentynoyl) analogues PYPAP and PYMAP. Rat hepatocytes converted APAP, AMAP, PYPAP, and PYMAP extensively to O-glucuronide and O-sulfate conjugates in varying proportions, whereas glutathione or cysteine conjugates were observed only for APAP and PYPAP...
October 13, 2016: Chemical Research in Toxicology
Ewa Barbier, Arnaud Lagorce, Amine Hachemi, Murielle Dutertre, Aurore Gorlas, Lucie Morand, Christine Saint-Pierre, Jean-Luc Ravanat, Thierry Douki, Jean Armengaud, Didier Gasparutto, Fabrice Confalonieri, Jean Breton
The hyperthermophilic archaeon Thermococcus gammatolerans can resist huge doses of γ-irradiation, up to 5.0 kGy, without loss of viability. The potential to withstand such harsh conditions is probably due to complementary passive and active mechanisms, including repair of damaged chromosomes. In this work, we documented the formation and repair of oxidative DNA lesions in T. gammatolerans. The basal level of the oxidized nucleoside, 8-oxo-2'-deoxyguanosine (8-oxo-dGuo), was established at 9.2 (± 0.9) 8-oxo-dGuo per 10(6) nucleosides, a higher level than those usually measured in eukaryotic cells or bacteria...
October 12, 2016: Chemical Research in Toxicology
Karan Uppal, Douglas I Walker, Ken Liu, Shuzhao Li, Young-Mi Go, Dean P Jones
"Sola dosis facit venenum." These words of Paracelsus, "the dose makes the poison", can lead to a cavalier attitude concerning potential toxicities of the vast array of low abundance environmental chemicals to which humans are exposed. Exposome research teaches that 80-85% of human disease is linked to environmental exposures. The human exposome is estimated to include >400,000 environmental chemicals, most of which are uncharacterized with regard to human health. In fact, mass spectrometry measures >200,000 m/z features (ions) in microliter volumes derived from human samples; most are unidentified...
October 12, 2016: Chemical Research in Toxicology
Bin Ma, Chris Ruszczak, Vipin Jain, Samir S Khariwala, Bruce Lindgren, Dorothy K Hatsukami, Irina Stepanov
Metabolic activation of the carcinogenic tobacco-specific N-nitrosamines leads to the formation of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts. We recently developed a liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method for the analysis of HPB-releasing DNA adducts in human oral cells. However, given the limited amounts of DNA that can be extracted from oral cells, higher sensitivity and selectivity are required for the reliable analysis of these adducts in future studies. We have developed a new sensitive LC-nanoelectrospray ionization-high-resolution MS/MS method for the analysis of HPB-releasing DNA adducts in oral cells...
October 12, 2016: Chemical Research in Toxicology
Sreekanth C Narayanapillai, Shang-Hsuan Lin, Pablo Leitzman, Pramod Upadhyaya, Carolyn J Baglole, Chengguo Xing
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a key carcinogen responsible for tobacco smoke-induced lung carcinogenesis. Among DNA damages caused by NNK and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), O6-methylguanine (O6-mG) is likely the most carcinogenic in A/J mice. Results of our previous studies showed that O6-mG and other NNAL-derived DNA damages were preferentially reduced in the lung of female A/J mice upon the dietary treatment with dihydromethysticin (DHM), a promising lung cancer chemopreventive agent from kava...
October 11, 2016: Chemical Research in Toxicology
Heather A Enright, Michael A Malfatti, Maike Zimmermann, Ted Ognibene, Paul Henderson, Kenneth W Turteltaub
Accelerator mass spectrometry (AMS) has been adopted as a powerful bioanalytical method for human studies in the areas of pharmacology and toxicology. The exquisite sensitivity (10(-18) mol) of AMS has facilitated studies of toxins and drugs at environmentally and physiologically relevant concentrations in humans. Such studies include risk assessment of environmental toxicants, drug candidate selection, absolute bioavailability determination, and more recently, assessment of drug-target binding as a biomarker of response to chemotherapy...
October 11, 2016: Chemical Research in Toxicology
Tiffany M Scharadin, Hongyong Zhang, Maike Zimmermann, Sisi Wang, Michael A Malfatti, George D Cimino, Kenneth Turteltaub, Ralph de Vere White, Chong-Xian Pan, Paul T Henderson
Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. We determined whether subtherapeutic "microdoses" of gemcitabine are incorporated into DNA at levels that correlate to drug cytotoxicity. A pair of nearly isogenic bladder cancer cell lines differing in resistance to several chemotherapy drugs were treated with various concentrations of (14)C-labeled gemcitabine for 4-24 h. Drug incorporation into DNA was determined by accelerator mass spectrometry. A mechanistic analysis determined that RRM2, a DNA synthesis protein and a known resistance factor, substantially mediated gemcitabine toxicity...
October 10, 2016: Chemical Research in Toxicology
John E Casida, Kathleen A Durkin
Pesticide researchers are students of nature, and each new compound and mechanism turns a page in the ever-expanding encyclopedia of life. Pesticides are both probes to learn about life processes and tools for pest management to facilitate food production and enhance health. In contrast to some household and industrial chemicals, pesticides are assumed to be hazardous to health and the environment until proven otherwise. About a thousand current pesticides working by more than 100 different mechanisms have helped understand many processes and coupled events...
October 7, 2016: Chemical Research in Toxicology
Tanzila Rehman, Mohd M Khan, Muhammad A Shad, Mazhar Hussain, Benjamin L Oyler, Young Ah Goo, David R Goodlett
This study was conducted to investigate the protein adducts with pesticides in a cohort of 172 factory workers that were exposed to a mixture of pesticides. The 35 samples showing considerable variation in biochemical parameters, i.e., butyrylcholinestrase (BChE), serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), gamma-glutamyl transferase (GGT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP/ALKP), lactate dehydrogenase (LDH), creatine phosphokinase (CPK) enzymes, and controls were analyzed by reversed-phase nanoscale liquid chromatography tandem mass spectrometry (nLC-MS/MS) on an Orbitrap mass spectrometer employing a shotgun proteomics approach...
October 6, 2016: Chemical Research in Toxicology
Adi Pinkas, Michael Aschner
Advanced glycation end-products (AGEs) are non-enzymatically glycated proteins, lipids and nucleic acids. These compounds both originate exogenously and are formed endogenously, and are associated, along with one of their receptors - RAGE, with a variety of pathologies and neurodegeneration. Some of their deleterious effects include affecting insulin signaling and FOXO-related pathways in both receptor-dependent and -independent manner. A potential ameliorating agent for these effects is insulin, which is being studied in several in vivo and in vitro models; one of these models is C...
October 5, 2016: Chemical Research in Toxicology
Kimberly Lapham, Jonathan Novak, Lisa D Marroquin, Rachel Swiss, Shuzhen Qin, Christopher J Strock, Renato Scialis, Michael D Aleo, Thomas Schroeter, Heather Eng, A David Rodrigues, Amit S Kalgutkar
Conjugated hyperbilirubinemia accompanied by cholestasis is a frequent side effect during chronic treatment with the antimicrobial agent fusidic acid. Previous studies from our laboratory, addressing mechanisms of musculoskeletal toxicity arising from coadministration of fusidic acid with statins, demonstrated the ability of fusidic acid to potently inhibit human organic anion transporting polypeptides OATP1B1 (IC50 = 1.6 μM) and OATP1B3 (IC50 = 2.5 μM), which are responsible for the uptake-limited clearance of statins as well as bilirubin glucuronide conjugates...
October 4, 2016: Chemical Research in Toxicology
Marcus J C Long, Yimon Aye
This perspective sets out to critically evaluate the scope of reactive electrophilic small molecules as unique chemical signal carriers in biological information transfer cascades. We consider these electrophilic cues as a new volatile cellular currency and compare them to canonical signaling circulation such as phosphate in terms of chemical properties, biological specificity, sufficiency, and necessity. The fact that nonenzymatic redox sensing properties are found in proteins undertaking varied cellular tasks suggests that electrophile signaling is a moonlighting phenomenon manifested within a privileged set of sensor proteins...
October 2, 2016: Chemical Research in Toxicology
Arun Tailor, James C Waddington, Xiaoli Meng, B Kevin Park
The covalent binding of drugs (metabolites) to proteins to form drug-protein adducts can have an adverse effect on the body. These adducts are thought to be responsible for idiosyncratic drug reactions including severe drug hypersensitivity reactions. Major advances in proteomics technology have allowed for the identification and quantification of target proteins for certain drugs. Human serum albumin (HSA) and Hb have been identified as accessible targets and potential biomarkers for drug-protein adducts formation, for numerous drugs (metabolites) including β-lactam antibiotics, reactive drug metabolites such as quinone imines (acetaminophen) and acyl glucuronides (diclofenac), and covalent inhibitors (neratinib)...
September 30, 2016: Chemical Research in Toxicology
Volker M Lauschke, Delilah F G Hendriks, Catherine C Bell, Tommy B Andersson, Magnus Ingelman-Sundberg
The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug metabolism and toxicity...
September 23, 2016: Chemical Research in Toxicology
Judy L Bolton, Tareisha L Dunlap
Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and carcinogenesis. In contrast, quinones can induce cytoprotection through induction of detoxification enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which quinones cause these effects can be quite complex. The various biological targets of quinones depend on their rate and site of formation and their reactivity...
September 12, 2016: Chemical Research in Toxicology
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