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  • Refinement of a Methodology for Untargeted Detection of Serum Albumin Adducts in Human Populations
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-17
    George W. Preston, Michelle Plusquin, Osman Sozeri, Karin van Veldhoven, Lilian Bastian, Tim S. Nawrot, Marc Chadeau-Hyam, David H. Phillips
    更新日期:2017-11-19
  • Assessment of anti-piperacillin IgG binding to structurally-related drug protein adducts
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-17
    Mohammed Amali, Rosalind Jenkins, Xioali Meng, Lee Faulkner, Paul Whitaker, Daniel Peckham, B. Kevin Park, Dean John Naisbitt

    The risk of developing hypersensitivity to alternative antibiotics is a concern for penicillin hypersensitive patients and healthcare pro-viders. Herein we use piperacillin hypersensitivity as a model to explore the reactivity of drug-specific IgG against alternative β-lactam protein adducts. Mass spectrometry was used to show the drugs (amoxicillin, flucloxacillin, benzyl penicillin, aztreonam and pipera-cillin) bind to similar lysine residues on the protein carrier bovine serum albumin. However, the hapten-specific IgG antibodies found in piperacillin hypersensitive patient plasma did not bind to other β-lactam protein conjugates. These data outline the fine specificity of piperacillin-specific IgG antibodies that circulate in patients with hypersensitivity.

    更新日期:2017-11-19
  • Nicotine Alters the Gut Microbiome and Metabolites of Gut–Brain Interactions in a Sex-Specific Manner
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-16
    Liang Chi, Ridwan Mahbub, Bei Gao, Xiaoming Bian, Pengcheng Tu, Hongyu Ru, Kun Lu
    更新日期:2017-11-17
  • Effects of Black Raspberry Extract and Berry Compounds on Repair of DNA Damage and Mutagenesis Induced by Chemical and Physical Agents in Human Oral Leukoplakia and Rat Oral Fibroblasts
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-15
    Joseph B. Guttenplan, Kun$L̫VxnLE$L̫VxnBraulio Lajara, Nora A. E. Shalaby, Wieslawa Kosinska, Gabrielle Benitez, Krishne Gowda, Shantu Amin, Gary Stoner, Karam El-Bayoumy
    更新日期:2017-11-16
  • Monoclonal antibody that recognizes diethoxyphospho-tyrosine modified proteins and peptides independent of surrounding amino acids
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-14
    Seda Onder, Alicia J. Dafferner, Lawrence M. Schopfer, Gaoping Xiao, Udaya Yerramalla, Ozden Tacal, Thomas A Blake, Rudolph C Johnson, Oksana Lockridge

    Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are irreversibly inhibited by organophosphorus pesticides through formation of a covalent bond with the active site serine. Proteins that have no active site serine, for example albumin, are covalently modified on tyrosine and lysine. Chronic illness from pesticide exposure is not explained by inhibition of AChE and BChE. Our goal was to produce a monoclonal antibody that recognizes proteins diethoxyphosphorylated on tyrosine. Diethoxyphosphate-tyrosine adducts for 13 peptides were synthesized. The diethoxyphosphorylated (OP) peptides crosslinked to 4 different carrier proteins were used to immunize, boost, and screen mice. Monoclonal antibodies were produced with hybridoma technology. Monoclonal depY was purified and characterized by ELISA, Western blotting, Biacore and Octet technology to determine binding affinity and binding specificity. DepY recognized diethoxyphospho-tyrosine independent of the amino acid sequence around the modified tyrosine and independent of the identity of the carrier protein or peptide. It had an IC50 of 3 x 10-9 M in a competition assay with OP tubulin. Kd values measured by Biacore and OctetRED96 were 10-8 M for OP-peptides and 1 x 10-12 M for OP-proteins. The limit of detection measured on Western blots hybridized with 0.14 µg/mL depY was 0.025 µg human albumin conjugated to YGGFL-OP. DepY was specific for diethoxyphospho-tyrosine (chlorpyrifos oxon adduct) as it failed to recognize diethoxyphospho-lysine, phospho-serine, phospho-tyrosine, phospho-threonine, dimethoxyphospho-tyrosine (dichlorvos adduct), dimethoxyphospho-serine, monomethoxyphospho-tyrosine (aged dichlorvos adduct), and cresylphospho-serine. In conclusion, a monoclonal antibody that specifically recognizes diethoxyphospho-tyrosine adducts has been developed. The depY monoclonal antibody could be useful for identifying new biomarkers of OP exposure.

    更新日期:2017-11-15
  • Methyl DNA Phosphate Adduct Formation in Rats Treated Chronically with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-13
    Bin Ma, Adam T. Zarth, Erik S Carlson, Peter W. Villalta, Pramod Upadhyaya, Irina Stepanov, Stephen S. Hecht

    The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a powerful lung carcinogen in animal models and is considered a causative factor for lung cancer in tobacco users. NNK is stereoselectively and reversibly metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is also a lung carcinogen. Both NNK and NNAL undergo metabolic activation by α-hydroxylation on their methyl groups to form pyridyloxobutyl and pyridylhydroxybutyl DNA base and phosphate adducts, respectively. α-Hydroxylation also occurs on the α-methylene carbons of NNK and NNAL to produce methane diazohydroxide, which reacts with DNA to form methyl DNA base adducts. DNA adducts of NNK and NNAL are important in their mechanisms of carcinogenesis. In this study, we characterized and quantified methyl DNA phosphate adducts in the lung of rats treated with 5 ppm of NNK, (S)-NNAL or (R)-NNAL in drinking water for 10, 30, 50 and 70 weeks, by using a novel liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method. A total of 23, 21 and 22 out of 32 possible methyl DNA phosphate adducts were detected in the lung tissues of rats treated with NNK, (S)-NNAL and (R)-NNAL, respectively. Levels of the methyl DNA phosphate adducts were 2290–4510, 872–1120, and 763–1430 fmol/mg DNA, accounting for 15–38%, 8%, and 5–9% of the total measured DNA adducts in rats treated with NNK, (S)-NNAL, and (R)-NNAL, respectively. The methyl DNA phosphate adducts characterized in this study further enriched the diversity of DNA adducts formed by NNK and NNAL. These results provide important new data regarding NNK- and NNAL-derived DNA damage, and new insights pertinent to future mechanistic and biomonitoring studies of NNK, NNAL, and other chemical methylating agents.

    更新日期:2017-11-14
  • Early Metabolome Profiling and Prognostic Value in Paraquat-Poisoned Patients: Based on Ultraperformance Liquid Chromatography Coupled To Quadrupole Time-of-Flight Mass Spectrometry
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-13
    Lufeng Hu, Guangliang Hong, Yahui Tang, Xianqin Wang, Congcong Wen, Feiyan Lin, Zhongqiu Lu

    Paraquat (PQ) has caused countless deaths throughout the world. There remains no effective treatment for PQ poisoning. Here we study the blood metabolome of PQ-poisoned patients using ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). Patients were divided into groups according to blood PQ concentration. Healthy subjects served as controls. Metabolic features were statistically analyzed using multivariate pattern-recognition techniques to identify the most important metabolites. Selected metabolites were further compared with a series of clinical indexes to assess the prognostic value. PQ-poisoned patients showed substantial differences compared with healthy subjects. Based on variable of importance in the project (VIP) values and statistical analysis, 17 metabolites were selected and identified. These metabolites well-classified low PQ-poisoned patients, high PQ-poisoned patients, and healthy subjects, which was better than that of a complete blood count (CBC). Among the 17 metabolites, 20:3/18:1-PC (PC), LPA (0:0/16:0) (LPA), 19-oxo-deoxycorticosterone (19-oxo-DOC), and eicosapentaenoic acid (EPA) had prognostic value. In particular, EPA was the most sensitive one. Besides, the levels of EPA was correlated with LPA and 19-oxo-DOC. If EPA was excessively consumed, then prognosis was poor. In conclusion, the serum metabolome is substantially perturbed by PQ poisoning. EPA is the most important biomarker in early PQ poisoning.

    更新日期:2017-11-13
  • Molecular Signatures Associated with Treatment of Triple-Negative MDA-MB231 Breast Cancer Cells with Histone Deacetylase Inhibitors JAHA and SAHA
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-12
    Mariangela Librizzi, Fabio Caradonna, Ilenia Cruciata, Janusz Dębski, Supojjanee Sansook, Michał Dadlez, John Spencer, Claudio Luparello
    更新日期:2017-11-13
  • Sulfide Toxicity and Its Modulation by Nitric Oxide in Bovine Pulmonary Artery Endothelial Cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-10
    Kristin L. Frawley, Andrea A. Cronican, Linda L. Pearce, Jim Peterson
    更新日期:2017-11-11
  • A Rapid Throughput Method to Extract DNA from Formalin-Fixed Paraffin-Embedded Tissues for Biomonitoring Carcinogenic DNA Adducts in Humans
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-09
    Byeong Hwa Yun, Shun Xiao, Lihua Yao, Sesha Krishnamachari, Thomas A. Rosenquist, Kathleen G. Dickman, Arthur P. Grollman, Paari Murugan, Christopher J. Weight, Robert J Turesky

    Formalin-fixed paraffin-embedded (FFPE) tissues are rarely used for screening DNA adducts of carcinogens because the harsh conditions required to reverse the formaldehyde-mediated DNA cross-links can destroy DNA adducts. We recently adapted a commercial silica-based column kit used in genomics to manually isolate DNA under mild conditions from FFPE tissues of rodents and humans and successfully measured DNA adducts of several carcinogens including aristolochic acid I (AA-I), 4-aminobiphenyl (4-ABP), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (Yun et al., (2013) Anal. Chem. 85:4251-8, and Guo et al. (2016) Anal. Chem. 88:4780-7). The DNA retrieval methodology is robust; however, the procedure is time-consuming and labor intensive, and not amenable to rapid throughput processing. In this study, we have employed the Promega Maxwell® 16 MDx system, which is commonly used in large scale genomics studies, for the rapid throughput extraction of DNA. This system streamlines the DNA isolation procedure and increases the sample processing rate by about eight-fold over the manual method (32 samples versus 4 samples processed per hour). High purity DNA is obtained in satisfactory yield for the measurements of DNA adducts by ultra performance liquid chromatography-electrospray-ionization-ion trap-multistage scan mass spectrometry. The measurements show that the levels of DNA adducts of AA-I, 4-ABP, and PhIP in FFPE rodent and human tissues are comparable to those levels measured in DNA from matching tissues isolated by the commercial silica-based column kits, and in DNA from fresh frozen tissues isolated by the conventional phenol-chloroform extraction method. The isolation of DNA from tissues is one major bottleneck in the analysis of DNA adducts. This rapid throughput methodology greatly decreases the time required to process DNA and can be employed in large-scale epidemiology studies designed to assess the role of chemical exposures and DNA adducts in cancer risk.

    更新日期:2017-11-09
  • The Relative Propensities of Cytochrome c Oxidase and Cobalt Corrins for Reaction with Cyanide and Oxygen: Implications for Amelioration of Cyanide Toxicity
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-08
    Quan Yuan, Linda Lorraine Pearce, Jim Peterson

    In aqueous media at neutral pH, the binding of two cyanide molecules per cobinamide can be described by two formation constants, Kf1 = 1.1 (±0.6) × 105 M-1 and Kf2 = 8.5 (±0.1) × 104 M-1, or an overall cyanide binding constant of ~1 × 1010 M-2. In comparison, the cyanide binding constants for cobalamin and a fully oxidized form of cytochrome c oxidase, each binding a single cyanide anion, were found to be 7.9 (±0.5) × 104 M-1 and 1.6 (±0.2) × 107 M-1, respectively. An examination of the cyanide-binding properties of cobinamide at neutral pH by stopped-flow spectrophotometry revealed two kinetic phases, rapid and slow, with apparent second-order rate constants of 3.2 (±0.5) × 103 M-1s-1 and 45 (±1) M-1s-1, respectively. Under the same conditions, cobalamin exhibited a single slow cyanide-binding kinetic phase with a second-order rate constant of 35 (±1) M-1s-1. All three of these processes are significantly slower than the rate at which cyanide is bound by complex IV during enzyme turnover (> 106 M-1s-1). Overall, it can be understood from these findings why cobinamide is a measurably better cyanide scavenger than cobalamin, but it is unclear how either cobalt corrin can be antidotal toward cyanide intoxication as neither compound, by itself, appears able to out-compete cytochrome c oxidase for available cyanide. Furthermore, it has also been possible to unequivocally show in head-to-head comparison assays that the enzyme does indeed have greater affinity for cyanide than both cobalamin and cobinamide. A plausible resolution of the paradox that both cobalamin and cobinamide clearly are antidotal toward cyanide intoxication, involving the endogenous auxiliary agent nitric oxide, is suggested. Additionally, the catalytic consumption of oxygen by the cobalt corrins is demonstrated and, in the case of cobinamide, the involvement of cytochrome c when present. Particularly in the case of cobinamide, these oxygen-dependent reactions could potentially lead to an erroneous assessment of the ability of the cyanide scavenger to restore the activity of cyanide-inhibited cytochrome c oxidase.

    更新日期:2017-11-09
  • Capture of cadmium by reactive polysulfides attenuates cadmium-induced adaptive responses and hepatotoxicity
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-08
    Masahiro Akiyama, Yasuhiro Shinkai, Takamitsu Unoki, Ilseob Shim, Isao Ishii, Yoshito Kumagai

    Cadmium (Cd) is an environmental electrophile modifying protein nucleophiles, thereby modulating cellular signaling and toxicity. While reactive persulfides/polysulfides exhibit relatively high nucleophilic properties, their roles in the altered gene expression and toxicity caused by Cd remain unclear. Exposing primary mouse hepatocytes to Cd caused heat shock protein 70 (HSP70) and metallothionein (MT)-I/II to be upregulated and cytotoxicity to occur. These effects were blocked in the presence of polysulfide sodium tetrasulfide (Na2S4). Electrospray ionization mass spectrometry analysis indicated that cadmium sulfide (CdS) and cadmium thiosulfate (CdS2O3) were produced when Cd reacted with Na2S4. Authentic CdS did not cause cellular signaling responses to be activated or hepatotoxic effects, while CdS2O3 caused similar effects of Cd. HSP70 and MT-I/II upregulation and hepatotoxicity caused by exposure to Cd were significantly enhanced by the deletion of cystathionine -lyase (CSE), which catalyzes the formation of reactive persulfides/polysulfides. Deleting CSE also exacerbated Cd-mediated liver injury, whereas little hepatic damage was found when CdS or Na2S4 along with Cd was administered. Overall, the results suggest that the persulfide/polysulfide-mediated formation of sulfur adducts of Cd such as CdS rather than CdS2O3 is, at least in part, involved in decreasing the Cd-mediated activation of cellular signaling and toxicity.

    更新日期:2017-11-09
  • Age-Dependent Effects of Acute Alcohol Administration in the Hippocampal Phosphoproteome
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-03
    Ana Contreras, Lidia Morales, Ali Tebourbi, Miguel Miguéns, Nuria del Olmo, Carmen Pérez-García
    更新日期:2017-11-05
  • Early metabolome profiling and prognostic value in paraquat poisoned patients: based on ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-03
    Lufeng Hu, Guangliang Hong, Yahui Tang, Xianqin Wang, Congcong Wen, Feiyan Lin, Zhongqiu Lu

    Paraquat (PQ) has caused countless deaths throughout the world. There remains no effective treatment for PQ poisoning. Here we study the blood metabolome of PQ-poisoned patient using ultra performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). Patients were divided into groups according blood PQ concentration. Healthy subjects served as controls. Metabolic features were statistically analyzed using multivariate pattern-recognition techniques to identify the most important metabolites. Selected metabolites were furtherly compared with a series of clinical indices to assess prognostic value. PQ-poisoned patients showed substantial differences compared with healthy subjects. Based on variable of importance in the project (VIP) values and statistical analysis, 17 metabolites were selected and identified. These metabolites well-classified low PQ poisoned patients, high PQ poisoned patients, and healthy subjects, which was better than did complete blood count (CBC). Among the 17 metabolites, 20:3/18:1-PC (PC), LPA (0:0/16:0) (LPA), 19-oxo-deoxycorticosterone (19-oxo-DOC), and eicosapentaenoic acid (EPA) had prognostic value. In particular, EPA was the most sensitive one. Besides, the levels of EPA was correlated with LPA and 19-oxo-DOC. If EPA was excessively consumed, prognosis was poor. In conclusion, the serum metabolome is substantially perturbed by PQ poisoning. EPA is the most important biomarker in early PQ poisoning.

    更新日期:2017-11-05
  • Refinement of a Methodology for Untargeted Detection of Serum Albumin Adducts in Human Populations
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-11-01
    George William Preston, Michelle Plusquin, Osman Sozeri, Karin van Veldhoven, Lilian Bastian, Tim S Nawrot, Marc Chadeau-Hyam, David H Phillips

    Covalently-modified blood proteins (e.g., serum albumin adducts) are increasingly being viewed as potential biomarkers via which the environmental causes of human diseases may be understood. The notion that some (perhaps many) modifications have yet to be discovered has led to the development of untargeted adductomics methods, which attempt to capture entire populations of adducts. One such method is fixed-step selected reaction monitoring (FS-SRM), which analyses distributions of serum albumin adducts via shifts in the mass of a tryptic peptide [Li et al. (2011) Mol. Cell. Proteomics 10, M110 004606]. Working on the basis that FS-SRM might be able to detect biological variation due to environmental factors, we aimed to scale the methodology for use in an epidemiological setting. Development of sample preparation methods led to a batch workflow with increased throughput and provision for quality control. Challenges posed by technical and biological variation were addressed in the processing and interpretation of the data. A pilot study of 20 smokers and 20 never-smokers provided evidence of an effect of smoking on levels of putative serum albumin adducts. Differences between smokers and never-smokers were most apparent in putative adducts with net gains in mass between 105 Da and 114 Da (relative to unmodified albumin). The findings suggest that our implementation of FS-SRM could be useful for studying other environmental factors with relevance to human health.

    更新日期:2017-11-02
  • Sulfide Toxicity and Its Modulation by Nitric Oxide in Bovine Pulmonary Artery Endothelial Cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-31
    Kristin L. Frawley, Andrea A. Cronican, Linda Lorraine Pearce, Jim Peterson

    Bovine pulmonary artery endothelial cells (BPAEC) respond in a dose-dependent manner to millimolar (0-10) levels of sodium sulfide (NaHS). No measurable increase in caspase-3 activity and no change in the extent of autophagy (or mitophagy) was observed in BPAEC. However, lactate dehydrogenase levels increased in the BPAEC exposed NaHS indicating necrotic cell death. In the case of galactose-conditioned BPAEC, the toxicity of NaHS was increased by 30% compared to that observed in BPAEC maintained in the regular glucose-containing culture medium, indicating a link between mitochondrial oxidative phosphorylation and the mechanism of toxicant action. This is consistent with the widely held view that cytochrome c oxidase (complex IV of the mitochondrial electron-transport system) is the principal molecular target involved in the acute toxicity of “sulfide” (H2S/HS–). In support of this view, elevated NO (which can reverse cytochrome c oxidase inhibition) ameliorated the toxicity of NaHS and, conversely, suppression of endogenous NO production exacerbated the observed toxicity. Respirometric measurements showed the BPAEC to possess a robust sulfide oxidizing system, which was able to out-compete cytochrome c oxidase for available H2S/HS– at micromolar concentrations. This detoxification system has previously been reported by other groups in several cell types, but notably, not neurons. The findings appear to provide some insight into the question of why human survivors of H2S inhalation frequently present at the clinic with respiratory insufficiency/pulmonary edema, while acutely poisoned laboratory animals tend to either succumb to cardiopulmonary paralysis or fully recover without any intervention.

    更新日期:2017-11-01
  • Dapsone and Nitroso Dapsone Activation of Naı̈ve T-Cells from Healthy Donors
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-31
    Abdulaziz Alzahrani, Monday Ogese, Xiaoli Meng, James C. Waddington, Arun Tailor, John Farrell, James L. Maggs, Catherine Betts, B. Kevin Park, Dean Naisbitt
    更新日期:2017-10-31
  • Potential Metabolic Activation of Representative Alkylated Polycyclic Aromatic Hydrocarbons 1-Methylphenanthrene and 9-Ethylphenanthrene Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-27
    Meng Huang, Clementina Mesaros, Linda C. Hackfeld, Richard P. Hodge, Ian A. Blair, Trevor M. Penning
    更新日期:2017-10-27
  • Active Site Interactions Impact Phosphoryl Transfer during Replication of Damaged and Undamaged DNA by Escherichia coli DNA Polymerase I
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-25
    A. S. Prakasha Gowda, Thomas E. Spratt
    更新日期:2017-10-26
  • Effects of Black Raspberry Extract and Berry Compounds on Repair of DNA Damage, and Mutagenesis Induced by Chemical and Physical Agents in Human Oral Leukoplakia and Rat Oral Fibroblasts
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-25
    Joseph Guttenplan, Kun-Ming Chen, Yuan-Wan Sun, Braulio Lajara, Nora AE Shalaby, Wieslawa Kosinska, Gabrielle Benitez, Krishne Gowda, Shantu Amin, Gary David Stoner, Karam El-Bayoumy

    Black raspberries (BRB) have been shown to inhibit carcinogenesis in a number of systems, with most studies focusing on progression. Previously we reported that an anthocyanin-enriched black raspberry extract (BE) enhanced repair of dibenzo[a,l]pyrene dihydrodiol (DBP-diol) induced DNA adducts and inhibited DBP-diol and DBP-diolepoxide (DBPDE)-induced mutagenesis in a lacI rat oral fibroblast cell line, suggesting a role for BRB in the inhibition of initiation of carcinogenesis. Here we extend this work to protection by BE, against DNA adduct formation induced by dibenzo[a,l]pyrene (DBP) in a human oral leukoplakia cell line (MSK) and to second carcinogen, UV light. Treatment of MSK cells with DBP and DBPDE led to a dose-dependent increase in DBP-DNA adducts. Treatment of MSK cells with BE after addition of DBP, reduced levels of adducts relative to cells treated with DBP alone; and treatment of rat oral fibroblasts with BE after addition of DBPDE, inhibited mutagenesis. These observations showed that BE affected repair of DNA adducts and not metabolism of DBP. As a proof of principle we also tested aglycones of two anthocyanins commonly found in berries, delphinidin chloride, and pelargonidin chloride. Delphinidin chloride reduced DBP-DNA adduct levels in MSK cells, while PGA did not. These results suggested that certain anthocyanins can enhance repair of bulky DNA adducts. As DBP and its metabolites induced formation of bulky DNA adducts, we investigated the effects of BE on genotoxic effects of a second carcinogen that induces bulky DNA damage, UV light. UV irradiation produced a dose-dependent increase in cyclobutanepyrimidine dimer levels in MSK cells, and post-UV treatment with BE resulted in lower cyclobutanepyrimidine dimer levels. Post-UV treatment of the rat lacI cells with BE reduced UV-induced mutagenesis. Taken together, the results demonstrate that BE extract reduces bulky DNA damage and mutagenesis, and support a role for BRB in the inhibition of initiation of carcinogenesis.

    更新日期:2017-10-26
  • AGE DEPENDENT EFFECTS OF ACUTE ALCOHOL ADMINISTRATION IN THE HIPPOCAMPAL PHOSPHOPROTEOME
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-24
    Ana Contreras, Lidia Morales, Ali Tebourbi, Miguel Miguéns, Nuria Del Olmo, Carmen Pérez García

    Alcohol consumption during adolescence is deleterious to the developing brain and leads to persistent deficits in adulthood. Several results provide strong evidence for ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the hippocampus. Protein phosphorylation is a well-known and well-documented mechanism in memory processes but information on phosphoprotein alterations in hippocampus after ethanol exposure is limited. This study focuses on age-related changes in the hippocampal phosphoproteome after acute alcohol administration. We have compared the phosphoprotein expression in the hippocampus of adult and adolescent Wistar rats treated with a single dose of ethanol (5 g/Kg i.p.), using a proteomic approach including phosphoprotein enrichment by immobilized metal affinity chromatography (IMAC). Our proteomic analysis revealed that 13 proteins were differentially affected by age, ethanol administration or both. Most of these proteins are involved in neuroprotection and are expressed less in young rats treated with ethanol. We conclude that acute alcohol induces important changes in the expression of phosphoproteins in the hippocampus that could increase the risk of neurodegenerative disorders, especially when the alcohol exposure begins in adolescence.

    更新日期:2017-10-25
  • Influence of DNA Lesions on Polymerase-Mediated DNA Replication at Single-Molecule Resolution
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-23
    Hailey L. Gahlon, Louis J. Romano, David Rueda
    更新日期:2017-10-23
  • Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-23
    Oliver P. Yockey, Vikash Jha, Pratibha P. Ghodke, Tianzuo Xu, Wenyan Xu, Hong Ling, P. I. Pradeepkumar, Linlin Zhao
    更新日期:2017-10-23
  • Active site interactions impact phosphoryl transfer during replication of damaged and undamaged DNA by Escherichia coli DNA Polymerase I
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-20
    A.S. Prakasha Gowda, Thomas E Spratt

    Replicative DNA polymerases are able to discriminate between very similar substrates with high accuracy. One mechanism by which Escherichia coli DNA polymerase I checks for Watson-Crick geometry is through a hydrogen bonding fork between Arg668 and the incoming dNTP and the minor groove of the primer terminus. The importance of the Arg-fork was examined by disrupting it with either a guanine to 3-deazaguanine substitution at the primer terminus or the use of a carbocyclic deoxyribose analog of dUTP. Using thio-substituted dNTPs and differential quench techniques, we determined that when the Arg-fork was disrupted, the rate limiting step changed from a conformational change to phosphodiester bond formation. This results indicates that Arg668 is involved in the phosphoryl transfer step We examined the role of the Arg-fork in the replication of four DNA damaged templates, O6-methylguanine (O6mG), 8-oxo-7,8-dihydroguanine (oxoG), O2-[4-(3-pyridyl)-4-oxobutyl]thymine (O2-POB-T), and N2-[(7S,8R,9S,10R)-7,8,9,10-tetrahydro-8,9,10-trihydroxybenzo[a]pyren-7-yl]-guanine (N2-BP-G). In general, the guanine to 3-deazaguanine substitution caused a decrease in kpol that was proportional to kpol over 5-orders of magnitude. The linear relationship indicates that the Arg668-fork helps catalyze phosphoryl transfer by the same mechanism with all the substrates. Exceptions to the linear relationship were the incorporations of dTTP opposite G, oxoG, and O6mG, which showed large decreases in kpol, similar to that exhibited by the Watson-Crick base pairs. It was proposed that the incorporation of dTTP opposite G, oxoG, and O6mG occurred via Watson-Crick-like structures.

    更新日期:2017-10-21
  • Dapsone and nitroso dapsone activation of naïve T-cells from healthy donors
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-18
    Abdulaziz Alzahrani, Monday O. Ogese, Xioali Meng, James Waddington, Arun Tailor, John Farrell, James L Maggs, Catherine J. Betts, B. Kevin Park, Dean John Naisbitt

    Dapsone (DDS) causes hypersensitivity reactions in 0.5-3.6% of patients. Although clinical diagnosis is indicative of a hypersensitivity reaction, studies have not been performed to define whether dapsone or a metabolite activates specific T-cells. Thus, the aims of this study were to explore the immunogenicity DDS and nitroso DDS (DDS-NO) using PBMC from healthy donors and splenocytes from mice and generate human T-cell clones to characterize mechanisms of T-cell activation. DDS-NO was synthesized from DDS-hydroxylamine and shown to bind to the thiol group of glutathione and human and mouse albumin through sulfonamide and N-hydroxyl sulphonamide adducts. Naïve T-cell priming to DDS and DDS-NO was successful in three human donors. DDS-specific CD4+ T-cell clones were stimulated to proliferate in response to drug via a MHC class II restricted direct binding interaction. Cross reactivity with DDS-NO, DDS-analogues and sulfonamides was not observed. DDS-NO clones were CD4+ and CD8+, MHC class II and I restricted, respectively, and activated via a pathway dependent on covalent binding and antigen processing. DDS and DDS-NO-specific clones secreted a mixture of Th1 and Th2 cytokines, but not granzyme-B. Splenocytes from mice immunized with DDS-NO were stimulated to proliferate in vitro with the nitroso metabolite, but not DDS. In contrast, immunization with DDS did not activate T-cells. These data show that DDS- and DDS-NO-specific T-cell responses are readily detectable.

    更新日期:2017-10-19
  • Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-19
    Tareisha L. Dunlap, Caitlin E. Howell, Nita Mukand, Shao-Nong Chen, Guido F. Pauli, Birgit M. Dietz, Judy L. Bolton
    更新日期:2017-10-19
  • Potential Metabolic Activation of Representative Alkylated Polycyclic Aromatic Hydrocarbons 1-Methylphenanthrene and 9-Ethylphenanthrene Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-16
    Meng Huang, Clementina A Mesaros, Linda C. Hackfield, Richard P. Hodge, Ian A Blair, Trevor M. Penning

    Exposure to petrogenic polycyclic aromatic hydrocarbons (PPAHs) is the major human health hazard associated with the Deepwater Horizon oil spill. Alkylated phenanthrenes are the most abundant PPAHs present in the crude oil and could contaminate the food chain. We describe the metabolism of a C1-phenanthrene regioisomer 1-methylphenanthrene (1-MP) and a C2-phenanthrene regioisomer 9-ethylphenanthrene (9-EP) in human HepG2 cells. The structures of the metabolites were identified by HPLC-UV-fluorescence detection and LC-MS/MS. Side chain hydroxylation of 1-MP and 9-EP was observed as the major metabolic pathway. The formation of 1-(hydroxymethyl)-phenanthrene was confirmed by reference to an authentic synthetic standard. However, formation of the bioactivated sulfate was not detected. Tetraols were also identified as signature metabolites of 1-MP and 9-EP, indicating that metabolic activation occurred via the diol-epoxide pathway. O-Monosulfonated-catechols were discovered as signature metabolites of the o-quinone pathway of metabolic activation of 1-MP and 9-EP, respectively. The identification of O-monosulfonated-catechols supports the metabolic activation of 1-MP and 9-EP by P450 and AKR isozymes followed by metabolic detoxification of the o-quinone through interception of redox cycling by phase II isozymes. The signature metabolites identified could be used as biomarkers of human exposure to 1-MP and 9-EP resulting from oil spills.

    更新日期:2017-10-17
  • Biotransformation of Isoniazid by Cytochromes P450: Analyzing the Molecular Mechanism using Density Functional Theory
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-16
    Chaitanya K. Jaladanki, Akbar Shaikh, Prasad V. Bharatam
    更新日期:2017-10-16
  • Nicotine alters the gut microbiome and metabolites of gut-brain interactions in a sex-specific manner
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-16
    Liang Chi, Ridwan Mahbub, Bei Gao, Xiaoming Bian, Pengcheng Tu, Hongyu Ru, Kun Lu

    As the primary active substance in tobacco, nicotine affects the activity of the central nervous system, and its effects are sex-dependent. There are complex interactions between the gut and brain, and the gut microbiome can influence neuronal activity and host behavior, with diverse chemical signaling being involved. However, it is unclear whether nicotine can affect the normal gut microbiome and associated chemical signaling of the gut-brain axis. Sex is an important factor that shapes the gut microbiome, but the role of sex in the interaction among nicotine, gut bacteria, and related metabolites remains unknown. In this study, we applied high-throughput sequencing and gas chromatography–mass spectrometry (GC-MS) to explore how nicotine exposure affects the gut microbiome and its metabolism in female and male C57BL/6J mice, with a focus on the chemical signaling involved in gut-brain interactions. 16S sequencing results indicated that the community composition of the gut microbiome was differentially perturbed by nicotine in females and males. Differential alterations of bacterial carbohydrate metabolic pathways are consistent with lower body weight gain in nicotine-treated males. Oxidative stress response and DNA repair genes were also specifically enriched in the nicotine-treated male gut microbiome. The fecal metabolome indicated that multiple neurotransmitters, such as glutamate, GABA and glycine, were differentially altered in female and male mice. Some neuroactive metabolites, including leucine and uric acid, were also changed. This study demonstrates a sex-dependent effect of nicotine on gut microbiome community composition, functional bacterial genes and the fecal metabolome.

    更新日期:2017-10-16
  • Influence of DNA Lesions on Polymerase-mediated DNA Replication at Single-Molecule Resolution
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-11
    Hailey Gahlon, Louis J. Romano, David Rueda

    Faithful replication of DNA is a critical aspect in maintaining genome integrity. DNA polymerases are responsible for replicating DNA, and high fidelity polymerases do this rapidly and at low error rates. For example, the holoenzyme of DNA polymerase III in E. coli can replicate at speeds of 600-1,000 bases per second and an error rate of 1 mistake per million nucleotides inserted.1-2 Upon exposure to exogenous or endogenous substances, DNA can become damaged and this can alter the speed and fidelity of a DNA polymerase. In this instance, DNA polymerases are confronted with an obstacle that can result in genomic instability during replication, for example by nucleotide misinsertion or replication fork collapse. It is important to know how DNA polymerases respond to damaged DNA substrates to understand the mechanism of mutagenesis and chemical carcinogenesis. Single-molecule techniques have helped to improve our current understanding of DNA polymerase-mediated DNA replication, as they enable the dissection of mechanistic details that can otherwise be lost in ensemble-averaged experiments. These techniques have also been used to gain a deeper understanding of how single DNA polymerases behave at the site of the damage in a DNA substrate. In this review, we evaluate single-molecule studies that have examined the interaction between DNA polymerases and damaged sites on a DNA template.

    更新日期:2017-10-12
  • Simultaneous Mass Spectrometric Analysis of Methylated and Ethylated Peptides in Human Hemoglobin: Correlation with Cigarette Smoking
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-12
    Hauh-Jyun Candy Chen, Sun Wai Ip, Fu-Di Lin
    更新日期:2017-10-12
  • Predicting Organ Toxicity Using in Vitro Bioactivity Data and Chemical Structure
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-09
    Jie Liu, Grace Patlewicz, Antony J. Williams, Russell S. Thomas, Imran Shah
    更新日期:2017-10-10
  • Red clover aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) agonists enhance genotoxic estrogen metabolism
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-06
    Tareisha L Dunlap, Caitlin E. Howell, Nita Mukand, Shao-Nong Chen, Guido F. Pauli, Birgit Maria Dietz, Judy L. Bolton

    Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women’s health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Non-malignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 µg/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist, ICI 182,780, potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in “normal” vs. breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism and the ER agonists downregulate the detoxification pathway. These data may suggest that especially breast cancer patients should avoid red clover and isoflavone based BDSs when making choices for menopausal symptom relief.

    更新日期:2017-10-07
  • A Chemoproteomic Platform To Assess Bioactivation Potential of Drugs
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-06
    Rui Sun, Fuguo Shi, Keke Liu, Ling Fu, Caiping Tian, Yong Yang, Keri A. Tallman, Ned A. Porter, Jing Yang
    更新日期:2017-10-06
  • Synthesis, Characterization, and Identification of New in Vitro Covalent DNA Adducts of Divinyl Sulfone, an Oxidative Metabolite of Sulfur Mustard
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-05
    Shanshan Lv, Yajiao Zhang, Bin Xu, Hua Xu, Yumei Zhao, Jia Chen, Zhongcai Gao, Jianfeng Wu, Jianwei Xie
    更新日期:2017-10-05
  • Detoxification of Atrazine by Low Molecular Weight Thiols in Alfalfa (Medicago sativa)
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-04
    Jing Jing Zhang, Jiang Yan Xu, Feng Fan Lu, She Feng Jin, Hong Yang
    更新日期:2017-10-04
  • Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-03
    Oliver Yockey, Vikash Jha, Pratibha P. Ghodke, Tianzuo Xu, Wenyan Xu, Hong Ling, Pushpangadan Indira Pradeepkumar, Linlin Zhao

    DNA damage impinges on genetic information flow and has significant implications in human disease and aging. Lucidin-3-O-primeveroside (LuP) is an anthraquinone derivative present in madder root, which has been used as a coloring agent and food additive. LuP can be metabolically converted to genotoxic compound lucidin, which subsequently forms lucidin-specific N2-2′-deoxyguanosine (N2-dG) and N6-2′-deoxyadenosine (N6-dA) DNA adducts. Lucidin is mutagenic and carcinogenic in rodents, but has low carcinogenic risks in humans. To understand the molecular mechanism of low carcinogenicity of lucidin in humans, we performed DNA replication assays using site-specifically modified oligonucleotides containing a structural analogue (LdG) of lucidin-N2-dG DNA adduct and determined the crystal structures of DNA polymerase (pol) κ in complex with LdG-bearing DNA and an incoming nucleotide. We examined four human pols (pol η, pol ι, pol κ, and Rev1) in their efficiency and accuracy during DNA replication with LdG; these pols are key players in DNA damage response. Our results demonstrate that pol κ efficiently and accurately replicates past the LdG adduct, whereas DNA replication by pol η, pol ι, and Rev1 is compromised to different extents. Two ternary crystal structures of pol κ illustrate that the LdG adduct is accommodated by pol κ at the enzyme active site during insertion and postlesion-extension steps. The unique open active site of pol κ allows the adducted DNA to adapt a standard B-form for accurate DNA replication. Collectively, these biochemical and structural data provide mechanistic insights into the low carcinogenic risk of lucidin in humans.

    更新日期:2017-10-04
  • Potential of Phenylbutyrate as Adjuvant Chemotherapy: An Overview of Cellular and Molecular Anticancer Mechanisms
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-03
    Maha S. Al-Keilani, Nour A. Al-Sawalha
    更新日期:2017-10-03
  • Simultaneous Mass Spectrometric Analysis of Methylated and Ethylated Peptides in Human Hemoglobin: Correlation with Cigarette Smoking
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-10-02
    Hauh-Jyun Candy Chen, Sun Wai Ip, Fu-Di Lin

    Alkylating agents contained in cigarettes smoke might be related to cancer development. Post-translational protein methylation and ethylation may cause alteration of protein functions. Human hemoglobin (Hb) has been a target for molecular dosimetry because of its easy accessibility. The goal of this study is to investigate the relationship between the levels of methylation and ethylation at specific sites of Hb with smoking. Because of the low extent of modification of Hb isolated from blood, the methylation and ethylation sites were identified in Hb incubated with a methylating agent (methyl methanesulfonate, MMS) and ethylating agent (ethyl methanesulfonate, EMS), respectively, by accurate mass measurements. After trypsin digestion, the modification sites were identified by nanoflow LC−nanospray ionization coupled with high-resolution mass spectrometry. The selected reaction monitoring (SRM) mode was used to quantify the relative extent of methylation and ethylation in human Hb incubated with MMS and EMS, respectively. Methylation occurred at 9 sites, including 1V, 20H, 50H, 72H of α-globin and 1V, 26E, 66K, 77H, 93C of β-globin. Ethylation was detected at 11 sites, including 1V, 16K, 50H, 72H, 87H of α-globin and 1V, 17K, 66K, 77H, 92H, 93C of β-globin. The relative extents of methylation and ethylation were measured in blood samples from 13 smokers and 13 nonsmokers. No statistically significant difference was found in the methylated peptides. On the other hand, the extents of ethylation at α-terminal Val, α-His-50, α-His-87, β-terminal Val, β-His-77, and β-Cys-93 in Hb were significantly higher in smokers than in nonsmokers (p < 0.05). Furthermore, the relative extents of ethylation at these sites were statistically significantly correlated with the number of cigarettes smoked per day. Therefore, this assay, which requires as little as one drop of blood, should be helpful in measuring Hb ethylation as a potential biomarker for assessing the exposure to cigarette smoking.

    更新日期:2017-10-03
  • A chemoproteomic platform to assess bioactivation potential of drugs
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-29
    Rui Sun, Fuguo Shi, Keke Liu, Ling Fu, Caiping Tian, Yong Yang, Keri A. Tallman, Ned A. Porter, Jing Yang

    Reactive metabolites (RM) formed from bioactivation of drugs can covalently modify liver proteins and cause mechanism-based inactivation of major cytochrome P450 (CYP450) enzymes. Risk of bioactivation of a test compound is routinely examined as part of lead optimization efforts in drug discovery. Here we described a chemoproteomic platform to assess in vitro and in vivo bioactivation potential of drugs. This platform enabled us to determine reactivity of thousands of proteomic cysteines toward RMs of diclo-fenac formed in human liver microsomes and living animals. We pinpointed numerous reactive cysteines as the targets of RMs of diclofenac, including the active (heme-binding) sites on several key CYP450 isoforms (1A2, 2E1 and 3A4 for human, 2C39 and 3A11 for mouse). This general platform should be applied to other drugs, drug candidates and xenobiotics with potential hepatoxicity, including environmental organic substances, bioactive natural products, and traditional Chinese medicine.

    更新日期:2017-10-01
  • Synthesis, Characterization and Identification of New In Vitro Covalent DNA Adducts of Divinyl Sulfone, an Oxidative Metabolite of Sulfur Mustard
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-29
    Shanshan Lv, Yajiao Zhang, Bin Xu, Hua Xu, Yumei Zhao, Jia Chen, Zhongcai Gao, Jianfeng Wu, Jianwei Xie

    Divinyl sulfone (DVS) is an important oxidative metabolic product of sulfur mustard (SM) in vitro and in vivo. Although DVS is not a classical blister agent, its high reactivity and toxicity induced by vinyl groups can also cause blisters like sulfur mustard upon contact with the skin, eyes, and respiratory organs. The purpose of this paper was to identify whether DVS could covalently bind to DNA bases to form new DNA adducts in cell in vitro s. A series of adducts were synthesized and characterized using purine, nucleoside or DNA, separately, as starting materials. The covalent site, pattern and relative reactivity of adduct formation were identified and discussed in detail. The results showed that five high abundance site-specific DNA adducts, including two monoadducts and three crosslinked adducts, were obtained when DNA was used as a substrate. When HaCaT cells were exposed to 30 μM of DVS, four new DNA adducts containing monoadducts and crosslinked adducts were found and identified in cells, including N3-A monoadduct, N7-G monoadduct, N7G-N7G bis-adduct and N3A-N7G crosslink adduct. Among them, the abundance of N3-A monoadduct was ten times higher than that those of the other three adducts. DNA adduct formation with DVS showed significant differences from that observed with SM. The observation of these new DNA adducts in vitro cells revealed that DNA damage could be also induced by DVS.

    更新日期:2017-10-01
  • “Juice Monsters”: Sub-Ohm Vaping and Toxic Volatile Aldehyde Emissions
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-29
    Soha Talih, Rola Salman, Nareg Karaoghlanian, Ahmad El-Hellani, Najat Saliba, Thomas Eissenberg, Alan Shihadeh
    更新日期:2017-10-01
  • Translesion DNA Synthesis in Cancer: Molecular Mechanisms and Therapeutic Opportunities
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-28
    Maroof K. Zafar, Robert L. Eoff
    更新日期:2017-09-29
  • Dose-Dependent Response to 3-Nitrobenzanthrone Exposure in Human Urothelial Cancer Cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-28
    Mario Pink, Nisha Verma, Anna Zerries, Simone Schmitz-Spanke
    更新日期:2017-09-29
  • A Multiplatform Approach for the Discovery of Novel Drug-Induced Kidney Injury Biomarkers
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-27
    Liuxi Chen, James Smith, Jaromir Mikl, Ryan Fryer, Frank Pack, Brad J. Williams, Jonathan A. Phillips, Vladimir V. Papov
    更新日期:2017-09-28
  • Transcriptomic Analysis of Thalidomide Challenged Chick Embryo Suggests Possible Link between Impaired Vasculogenesis and Defective Organogenesis
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-27
    Vimal Veeriah, Pavitra Kumar, Lakshmikirupa Sundaresan, Zeenath Mafitha, Ravi Gupta, Uttara Saran, Jeganathan Manivannan, Suvro Chatterjee
    更新日期:2017-09-28
  • Benchmark Dose Modeling Estimates of the Concentrations of Inorganic Arsenic That Induce Changes to the Neonatal Transcriptome, Proteome, and Epigenome in a Pregnancy Cohort
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-27
    Julia E. Rager, Scott S. Auerbach, Grace A. Chappell, Elizabeth Martin, Chad M. Thompson, Rebecca C. Fry
    更新日期:2017-09-28
  • Copper Inhibits the AlkB Family DNA Repair Enzymes under Wilson’s Disease Condition
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-26
    Ke Bian, Fangyi Chen, Zachary T. Humulock, Qi Tang, Deyu Li
    更新日期:2017-09-26
  • Immunopurification of Acetylcholinesterase from Red Blood Cells for Detection of Nerve Agent Exposure
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-25
    Alicia J. Dafferner, Lawrence M. Schopfer, Gaoping Xiao, John R. Cashman, Udaya Yerramalla, Rudolph C. Johnson, Thomas A. Blake, Oksana Lockridge
    更新日期:2017-09-25
  • “Juice monsters”: sub-ohm vaping and toxic volatile aldehyde emissions
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Soha Talih, Rola Salman, Nareg Karaoghlanian, Ahmad El-Hellani, Najat Aoun Saliba, Thomas Eissenberg, Alan Shihadeh

    An emerging category of electronic cigarettes (ECIGs) are sub-Ohm devices (SODs) that operate at ten or more times the power of conventional ECIGs. Because carcinogenic volatile aldehyde (VAs) emissions increase sharply with power, SODs may expose users to greater VAs. In this study, we compared VA emissions from several SODs and found that across device, VAs and power were un-correlated unless power was normalized by coil surface area. VA emissions and liquid consumed were correlated highly. Analyzed in light of EU regulations limiting ECIG liquid nicotine concentration, these findings suggest potential regulatory levers and pitfalls for protecting public health.

    更新日期:2017-09-23
  • Investigation of Dioscorea bulbifera Rhizome-Induced Hepatotoxicity in Rats by a Multisample Integrated Metabolomics Approach
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Dong-Sheng Zhao, Li-Long Jiang, Ya-Xi Fan, Ling-Li Wang, Zhuo-Qing Li, Wei Shi, Ping Li, Hui-Jun Li
    更新日期:2017-09-23
  • Coordination and Substitution of DNA Polymerases in Response to Genomic Obstacles
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Michael A. Trakselis, Matthew T. Cranford, Aurea M. Chu
    更新日期:2017-09-23
  • Multidrug Resistance Protein 4 (MRP4/ABCC4) Protects Cells from the Toxic Effects of Halobenzoquinones
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Jinhua Li, Madlen Bauer, Birget Moe, Elaine M. Leslie, Xing-Fang Li
    更新日期:2017-09-22
  • Detoxification of atrazine by low molecular weight thiols in alfalfa (Medicago sativa)
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-21
    Jing Jing Zhang, Jiang-Yan Xu, Feng Fan Lu, She Feng Jin, Hong Yang

    Low molecular weight (LMW) thiols in higher plants are a group of sulfur-rich non-protein compounds and play primary and multiple roles in cellular redox homeostasis, enzyme activities, and xenobiotics detoxification. This study focused on identifying thiols-related protein genes from the legume alfalfa exposed to the herbicide atrazine (ATZ) residues in environment. Using high-throughput RNA-sequencing, a set of ATZ-responsive thiols-related protein genes highly up-regulated and differentially expressed in alfalfa were identified. Most of the differentially expressed genes (DEGs) were involved in regulation of biotic and abiotic stress responses. By analyzing the genes involved in thiols-mediated redox homeostasis, we found that many of them were thiols-synthetic enzymes such as γ-glutamylcysteine synthase (γECS), homoglutathione synthetase (hGSHS) and glutathione synthetase (GSHS). Using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), we further characterized a group of ATZ-thiols conjugates, which are the detoxified forms of ATZ in plants. Cysteine S-conjugate ATZ-HCl+Cys was the most important metabolite detected by the mass spectrometry. Several other ATZ-conjugates were also examined as ATZ-detoxified metabolites. Such results were validated by characterizing their analogs in rice. Our data showed that some conjugates under ATZ stress were detected in both plants, indicating that some detoxified mechanisms and pathways can be shared by the two plant species. Overall, these results indicate that LMW thiols play critical roles in detoxification of ATZ in the plants.

    更新日期:2017-09-21
  • Hemoglobin Adducts and Urinary Metabolites of Arylamines and Nitroarenes
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-21
    Gabriele Sabbioni
    更新日期:2017-09-21
  • The potential of phenylbutyrate as adjuvant chemotherapy: an overview of cellular and molecular anticancer mechanisms
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-20
    Maha Al-Keilani, Nour A. Al-Sawalha

    Despite the advancement in cancer therapy, a high number of patients fail treatment because of drug resistance. Several preclinical in vitro data suggest that phenylbutyrate has antiproliferative, antiangiogenic, antimetastatic, immunomodulatory, and differentiating properties. Moreover, phenylbutyrate administration in vivo provided an oncoprotective effect. However, the results of clinical trials indicate that the antineoplastic potential of phenylbutyrate is hindered by its pharmacokinetic and pharmacodynamic properties. Thus, understanding the exact mechanisms of the anticancer effect of phenylbutyrate could assist in the selection of patients who will best benefit from this drug. The present review discusses the proposed mechanisms of antineoplastic effect of phenylbutyrate and the preclinical and clinical evidences suggesting its potential role as anticancer in different types of cancer.

    更新日期:2017-09-20
  • Benchmark Dose Modeling Estimates of the Concentrations of Inorganic Arsenic that Induce Changes to the Neonatal Transcriptome, Proteome and Epigenome in a Pregnancy Cohort
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-19
    Julia Rager, Scott S. Auerbach, Grace A Chappell, Elizabeth Martin, Chad Thompson, Rebecca C Fry

    Prenatal inorganic arsenic (iAs) exposure influences the expression of critical genes and proteins associated with adverse outcomes in newborns, in part through epigenetic mediators. The doses at which these genomic and epigenomic changes occur have yet to be evaluated in the context of dose-response modeling. The goal of the present study was to estimate iAs doses that correspond to changes in transcriptomic, proteomic, epigenomic, and integrated multi-omic signatures in human cord blood through benchmark dose (BMD) modeling. Genome-wide DNA methylation, microRNA expression, mRNA expression, and protein expression levels in cord blood were modeled against total urinary arsenic (U-tAs) levels from pregnant women exposed to varying levels of iAs. Dose-response relationships were modeled in BMDExpress, and BMDs representing 10% response levels were estimated. Overall, DNA methylation changes were estimated to occur at lower exposure concentrations in comparison to other molecular endpoints. Multi-omic module eigengenes were derived through weighted gene co-expression network analysis, representing co-modulated signatures across transcriptomic, proteomic, and epigenomic profiles. One module eigengene was associated with decreased gestational age occurring alongside increased iAs exposure. Genes/proteins within this module eigengene showed enrichment for organismal development, including potassium voltage-gated channel subfamily Q member 1 (KCNQ1), an imprinted gene showing differential methylation and expression in response to iAs. Modeling of this prioritized multi-omic module eigengene resulted in a BMD(BMDL) of 58(45) µg/L U-tAs, which was estimated to correspond to drinking water arsenic concentrations of 51(40) µg/L. Results are in line with epidemiological evidence supporting effects of prenatal iAs occurring at levels <100 µg As/L urine. Together, findings present a variety of BMD measures to estimate doses at which prenatal iAs exposure influences neonatal outcome-relevant transcriptomic, proteomic and epigenomic profiles.

    更新日期:2017-09-20
  • Copper Inhibits the AlkB Family DNA Repair Enzymes under Wilson’s Disease Condition
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-19
    Ke Bian, Fangyi Chen, Zachary T. Humulock, Qi Tang, Deyu Li

    Disturbed metabolism of copper ions can cause diseases, such as Wilson’s disease (WD). In this work, we investigated the inhibi-tory effect of Cu(II) ion on the AlkB family DNA repair enzymes in vitro, which are members of the Fe(II)/alpha-ketoglutarate-dependent dioxygenase and include human ALKBH2, ALKBH3, and E. coli AlkB proteins. None of the three proteins were significantly inhibited under normal cellular copper concentrations. But under WD related condition, we observed the activities of all three enzymes were strongly suppressed (from 95.2 to 100.0%). We also noted the repair efficiency under ds-DNA condition is less susceptible than ss-DNA to the inhibition.

    更新日期:2017-09-20
  • Dose-dependent response to 3-nitrobenzanthrone exposure in human urothelial cancer cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-18
    Mario Pink, Nisha Verma, Anna Zerries, Simone Schmitz-Spanke

    A product of incomplete combustion of diesel fuel, 3-nitrobenzanthrone (3-NBA), has been classified as a cancer-causing substance. It first gained attention as a potential urinary bladder carcinogen due to the presence of its metabolite in urine and formation of DNA adducts. The aim of the present study was to characterise the dose-response relationship of 3-NBA in human urothelial cancer cell line (RT4) exposed to concentrations ranging from 0.0003 µM (environmentally relevant) to 80 µM by utilising toxicological and metabolomic approaches. We observed that the RT4 cells were capable of bioactivation of 3-NBA within 30 minutes of exposure. Activity measurements of various enzymes involved in the conversion of 3-NBA in RT4 cells demonstrated NAD(P)H:quinone oxidoreductase (NQO1) as the main contributor for its bioactivation. Moreover, cytotoxicity assessment exhibited an initiation of adaptive mechanisms at low dosages, which diminished at higher doses, indicating that the capacity of these mechanisms no longer suffices - resulting in increased levels of intracellular reactive oxygen species, reduced proliferation and hyperpolarisation of the mitochondrial membrane. To characterise the underlying mechanisms of this cellular response, the metabolism of 3-NBA and metabolomic changes in the cells were analysed. The metabolomic analysis of the cells (0.0003, 0.01, 0.08, 10, and 80 µM 3-NBA) showed elevated levels of various antioxidants at low concentrations of 3-NBA. Whereas, at higher exposure concentrations, it appeared that the cells reprogrammed their metabolism to maintain the cell homeostasis via activation of pentose phosphate pathway (PPP).

    更新日期:2017-09-19
  • 更新日期:2017-09-15
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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