Chemical Research in Toxicology (CHEM RES TOXICOL)

Publisher: American Chemical Society; International Society for the Study of Xenobiotics, American Chemical Society

Journal description

This timely, international journal is intended to provide a forum for presentation of research relevant to all aspects of the chemical basis of toxicological responses. It publishes papers devoted to identification of novel toxic agents and reactive intermediates, development of specific and sensitive new methods for detection of modification of biological macromolecules by toxic agents, characterization of the alteration of macromolecular structure and function by interaction with chemical agents, experimental and theoretical studies of chemical factors that control reactivity with specific macromolecules, and metabolism of toxic agents as it contributes to their biological effects. Chemical Research in Toxicology publishes Articles, Communications, Invited Reviews, and Perspectives on structural, mechanistic, and technological advances in research related to the toxicological effects of chemical agents. In addition, a feature entitled Forum is published once a year.

Current impact factor: 3.53

Impact Factor Rankings

2016 Impact Factor Available summer 2017
2014 / 2015 Impact Factor 3.529
2013 Impact Factor 4.19
2012 Impact Factor 3.667
2011 Impact Factor 3.779
2010 Impact Factor 4.148
2009 Impact Factor 3.74
2008 Impact Factor 3.491
2007 Impact Factor 3.508
2006 Impact Factor 3.162
2005 Impact Factor 3.339
2004 Impact Factor 2.797
2003 Impact Factor 3.332
2002 Impact Factor 3.607
2001 Impact Factor 3.179
2000 Impact Factor 3.187
1999 Impact Factor 3.47
1998 Impact Factor 3.336
1997 Impact Factor 2.919
1996 Impact Factor 3.19
1995 Impact Factor 3.025
1994 Impact Factor 3.395
1993 Impact Factor 3.374
1992 Impact Factor 4.064

Impact factor over time

Impact factor
Year

Additional details

5-year impact 3.62
Cited half-life 7.40
Immediacy index 0.66
Eigenfactor 0.02
Article influence 0.97
Website Chemical Research in Toxicology website
Other titles Chemical research in toxicology, Chemical research in toxicology. Supporting information
ISSN 0893-228X
OCLC 15464975
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

American Chemical Society

  • Pre-print
    • Author cannot archive a pre-print version
  • Restrictions
    • Must obtain written permission from Editor
    • Must not violate ACS ethical Guidelines
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • If mandated by funding agency or employer/ institution
    • If mandated to deposit before 12 months, must obtain waiver from Institution/Funding agency or use AuthorChoice
    • 12 months embargo
  • Conditions
    • On author's personal website, pre-print servers, institutional website, institutional repositories or subject repositories
    • Non-Commercial
    • Must be accompanied by set statement (see policy)
    • Must link to publisher version
    • Publisher's version/PDF cannot be used
    • If mandated sooner than 12 months, must obtain waiver from Editors or use AuthorChoice
    • Reviewed on 07/08/2014
  • Classification
    white

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Nicotine is the most abundant alkaloid in tobacco accounting for 95% of the alkaloid content. There are also several minor tobacco alkaloids, among these are nornicotine, anatabine and anabasine. We developed and applied a 96 well plate-based capillary LC-tandem mass spectrometry method for the analysis of nornicotine, anatabine and anabasine in urine. The method was validated with regard to accuracy and precision. Anabasine was quantifiable to low levels with a limit of quantitation (LOQ) of 0.2 ng/ml even when nicotine, which is isobaric, is present at concentrations >2500-fold higher than anabasine. This attribute of the method is important since anatabine and anabasine in urine have been proposed as biomarkers of tobacco use for individuals using nicotine replacement therapies. In the present study, we analyzed the three minor tobacco alkaloids in urine from 827 smokers with a wide range of tobacco exposures. Nornicotine (LOQ 0.6 ng/ml) was detected in all samples and anatabine (LOQ, 0.15 ng/ml) and anabasine were detected in 97.7% of the samples. The median urinary concentrations of nornicotine, anatabine and anabasine were 98.9, 4.02 and 5.53 ng/ml. Total nicotine equivalents (TNE) were well correlated with anatabine (r2 = 0.714) and anabasine (r2 = 0.760). TNE was most highly correlated with nornicotine, which is also a metabolite of nicotine. Urine samples from a subset of subjects (n = 110) were analyzed for the presence of glucuronide conjugates by quantifying any increase in anatabine and anabasine concentrations after β-glucuronidase treatment. The median ratio of the glucuronidated to free anatabine was 0.74 (range, 0.1 to 10.9) and the median ratio of glucuronidated to free anabasine was 0.3 (range, 0.1 to 2.9). To our knowledge this is the largest population of smokers for whom the urinary concentrations of these three tobacco alkaloids has been reported.
    No preview · Article · Jan 2016 · Chemical Research in Toxicology
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    ABSTRACT: Pyrrolizidine alkaloids (PAs) are known hepatotoxins. The execution of the toxicities of the alkaloids requires metabolic activation. Protein modification by reactive metabolites of PAs has been suggested to be an important mechanism of the toxic actions of PAs. The objectives of the present study were to define the interactions of dehydromonocrotaline (DHM) with lysine, lysine derivatives, a model peptide, and bovine serum albumin and to explore the lysine modification of hepatic proteins of animals given monocrotaline. DHM was found to react with -amino group of all model compounds tested after incubation with DHM, and the modification reaction preferentially occurred at C7 of the necine base. The lysine residue modification with the same regioselectivity was also observed in hepatic proteins of mice treated with monocrotaline. The observed modification increased with the increasing in the doses administered in the animals. This work allowed us to better understand the mechanisms of hepatotoxicity of monocrotaline.
    No preview · Article · Jan 2016 · Chemical Research in Toxicology
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    ABSTRACT: Methylglyoxal (MG) is a highly reactive dicarbonyl compound involved in the formation of advanced glycation endproducts. Levels of MG are elevated in patients with type-2 diabetes mellitus (T2DM), and advanced glycation endproducts (AGEs) have been implicated in the progression of diabetic complications. The anti-hyperglycemic drug metformin (MF) has been suggested to be a scavenger of MG. The present work examined and characterized unequivocally the resulting scavenged product from the metformin-MG reaction. The primary product was characterized by 1H, 13C, 2D-HSQC and HMBC NMR, and tandem mass spectrometry. X-ray diffraction (XRD) analysis determined the structure of the metformin and MG-derived imidazolinone compound to be (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)guanidine (IMZ). A LC-MS/MS multiple reaction monitoring method was developed to detect and quantify the presence of IMZ in metformin-treated T2DM patients. Urine from >90 MF-treated T2DM patients was analyzed, with increased levels of MF directly correlating with elevations in IMZ. Urinary MF was detected in the range of 0.17 μM - 23.0 mM, and simultaneous measurement of IMZ concentrations were in the range of 18.8 nM to 4.3 μM. Since plasma concentrations of MG range from 40 nM to 4.5 μM the level of IMZ production may be of therapeutic significance. Thus, in addition to lowering hepatic gluconeogenesis, metformin also scavenges the highly reactive MG in vivo, thereby reducing potentially detrimental MG protein adducts, with subsequent reductions in diabetic complications.
    No preview · Article · Jan 2016 · Chemical Research in Toxicology
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    ABSTRACT: Frameshift mutagenesis encompasses the gain or loss of DNA base pairs, resulting in altered genetic outcomes. The NarI restriction site sequence 5'-G1G2CG3CX-3' in Escherichia coli is a well-known mutational hotspot, in which lesioning of acetylaminofluorene (AAF) at G3* induces a greater -2 deletion frequency than that at other guanine sites. Its mutational efficiency is modulated by the nature of the nucleotide in the X position (C ~ A > G > T). Here, we conducted a series of polymerase-free solution experiments that examine the conformational and thermodynamic basis underlying the propensity of adducted G3 to form a slipped mutagenic intermediate (SMI) and its sequence dependence during translesion synthesis (TLS). Instability of the AAF-dG3:dC pair at the replication fork promoted a slippage to form a G*C bulge-out SMI structure, consisting of S- ("lesion stacked") and B-SMI ("lesion exposed") conformations, with conformational rigidity increasing as a function of primer elongation. We found greater stability of the S- compared to the B-SMI conformer throughout TLS. The dependence of their population ratios was determined by the 3'-next flanking base X at fully elongated bulge structures, with 59% B/41% S and 86% B/14% S for the dC and dT series, respectively. These results indicate the importance of direct interactions of the hydrophobic AAF lesion with the 3'-next flanking base pair and its stacking fit within the -2 bulge structure. A detailed conformational understanding of the SMI structures and their sequence dependence may provide a useful model for DNA polymerase complexes.
    No preview · Article · Jan 2016 · Chemical Research in Toxicology
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    ABSTRACT: N,N-bis-(2-chloroethyl)-phosphorodiamidic acid (phosphoramide mustard, PM) and N,N-bis-(2-chloroethyl)-ethylamine (nornitrogen mustard, NOR) are the two biologically active metabolites of cyclophosphamide, a DNA alkylating drug commonly used to treat lymphoma, breast cancer, certain brain cancers, and autoimmune diseases. PM and NOR are reactive bis-electrophiles capable of cross-linking cellular biomolecules to form covalent DNA-DNA and DNA-protein cross-links (DPCs). In the present work, a mass spectrometry-based proteomics approach was employed to characterize PM- and NOR-mediated DNA-protein cross-linking in human cells. Following treatment of human fibrosarcoma cells (HT1080) with cytotoxic concentrations of PM, over 130 proteins were found to be covalently trapped to DNA, including those involved in transcriptional regulation, RNA splicing/processing, chromatin organization, and protein transport. HPLC-ESI+-MS/MS analysis of proteolytic digests of DPC-containing DNA from NOR-treated cells revealed a concentration-dependent formation of N-[2-[cysteinyl]ethyl]-N-[2-(guan-7-yl)ethyl]amine (Cys-NOR-N7G) conjugates, confirming that it cross-links cysteine thiols of proteins to the N-7 position of guanines in DNA. Cys-NOR-N7G adduct numbers were higher in NER-deficient Xeroderma pigmentosum cells (XPA) as compared with repair proficient cells. Furthermore, both XPA and FANCD2 deficient cells were sensitized to NOR treatment as compared to wild type cells, suggesting that Fanconi Anemia and nucleotide excision repair pathways are involved in the removal of cyclophosphamide-induced DNA damage.
    No preview · Article · Dec 2015 · Chemical Research in Toxicology
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    ABSTRACT: The Co(III)-containing water-soluble metalloporphyrin cobalt(III) meso-tetra(4-N-methylpyridyl)porphine triiodide (CoIIITMPyP) is a potential cyanide scavenging agent. The rate of reduction of Co(III)TMPyP by ascorbate is facile enough that conversion to the Co(II)-containing CoIITMPyP should occur within minutes at prevailing in vivo levels of the reductant. It follows that any cyanide-decorporating capability of the metalloporphyrin should depend more on the cyanide-binding characteristics of Co(II)TMPyP rather than those of the administered form Co(III)TMPyP. Addition of cyanide to buffered aqueous solutions of Co(II)TMPyP (pH 7.4, 25-37ºC) results in quite rapid (k2 = ~103 M-1s-1) binding/substitution of cyanide anion in the two available axial positions with high affinity (Kß = 1010-1011). Electron paramagnetic resonance (EPR) spectroscopic measurements and cyclic voltammetry (CV) indicate that cyanide induces oxidation to the Co(III)-containing dicyano species. The constraints that these observations put on plausible mechanisms for the reaction of Co(II)TMPyP with cyanide are discussed. Experiments in which CoIIITMPyP and cyanide were added to freshly drawn mouse blood showed the same sequence of reactions (metalloporphyrin reduction -> cyanide binding/substitution -> re-oxidation) to occur. Therefore, in cyanide-scavenging applications with this metalloporphyrin, we should be taking advantage of both the improved rate of ligand substitution at Co(II) compared to Co(III) and, also, the increased affinity of Co(III) for anionic ligands compared to Co(II). Finally, using an established sub-lethal mouse model for cyanide intoxication, Co(III)TMPyP, administered either 5 min before (prophylaxis) or 1 min after the toxicant, is shown to have very significant antidotal capability. Possible explanations for the results of a previous contradictory study, which failed to find any prophylactic effect of Co(III)TMPyP towards cyanide intoxication, are considered.
    No preview · Article · Dec 2015 · Chemical Research in Toxicology
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    ABSTRACT: Aristolochic acid (AA) is a natural bioactive substance found in Chinese herbs, which induce toxicity during ovarian maturation of animals and humans. Apoptosis, which is induced by various damages, is a rapid, selective process of physiological cell deletion that regulates the balance between cell proliferation and death. However, the mechanism of AA toxicity during testis maturation in the mouse has not been elucidated, and was thus the subject of the present investigation. We used TM4 Sertoli cells and an ICR mouse model, both of which were injected with aristolochic acid I (AAI) for 4 weeks. Testis size and weight were measured to determine AAI toxicity in the mouse testis. Cytotoxicity of AAI in TM4 Sertoli cells was analyzed by the MTT assay. The expression of apoptosis mediators was measured by western blotting while the measure of apoptotic cell death in TM4 Sertoli cells and testis tissue was analyzed by the TUNEL assay. We found that the viability of TM4 Sertoli cells was strongly inhibited by AAI, and that apoptotic cell death was significantly induced by AAI in TM4 Sertoli cells and mouse testis tissue. In addition, AAI suppressed the expression of B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein. It markedly improved the expression of pro-apoptotic proteins including poly (ADP-ribose) polymerase, Bcl-2-associated X protein, and caspase-3 and 9. Furthermore, we observed that AAI significantly reduced the size and weight of mouse testis. Moreover, the germ cells and somatic cells in testis were markedly damaged by AAI. In addition, we found that AAI significantly inhibited Akt and ERK1/2 phosphorylation in TM4 Sertoli cells and testis tissue. These results suggest that AAI causes severe damage during testis maturation by inhibiting Akt and ERK1/2 phosphorylation-mediated apoptosis.
    No preview · Article · Dec 2015 · Chemical Research in Toxicology
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    ABSTRACT: Globally, maternal and fetal health is greatly impacted by extraplacental inflammation. Group B streptococcus (GBS), a leading cause of chorioamnionitis, is thought to take advantage of the uterine environment during pregnancy in order to cause inflammation and infection. In this study, we demonstrate the metabolic changes of murine macrophages caused by GBS exposure. GBS alone prompted a delayed increase in lactate production, highlighting its ability to redirect macrophage metabolism from aerobic to anaerobic respiration. This production of lactate is thought to aid in the development and propagation of GBS throughout the surrounding tissue. Additionally, this study shows that PGE2 priming was able to exacerbate lactate production, shown by the rapid and substantial lactate increases seen upon GBS exposure. These data provide a novel model to study the role of GBS exposure to macrophages with and without PGE2 priming.
    No preview · Article · Dec 2015 · Chemical Research in Toxicology
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    ABSTRACT: Oxidative damage is one of the most frequent types of DNA damage resulting from biologically generated oxygen or nitrogen reactive species. Hydroxyl radicals, one electron oxidants, and various chemical oxidants, such as permanganate and ozone, react with pyrimidine bases in DNA, cytosine and thymine, to produce 5-hydroxyhydantoin derivatives. 5-Hydroxyhydantoin modifications are interesting because they undergo ring-chain tautomerism into a pair of diastereomers via an open chain carbonyl intermediate. Here, we show that purified diastereomers of N1-(2-Deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin not only undergo isomerization into a mixture of 5R and 5S diastereomers of the hydantoin ring but also into three additional pairs of diastereomers, in which the sugar moiety transforms into α-furanose, β-pyranose and α-pyranose anomers. The novel 5-hydroxy-5-methylhydantoin derivatives were characterized by extensive NMR analyses. Further studies indicate that isomerization is greatly suppressed at pH 6 compared to that at higher pH likely due to protonation of the open chain intermediate. A novel mechanism of isomerization is proposed to account for the formation of nucleoside anomers at neutral pH, which involves ring-chain tautomerism of both the hydantoin and sugar moieties. Lastly, the isomerization of β-furanose into the corresponding α-furanose is shown to take place in purified DNA albeit to a slower extent than that in solution. The ability of 5-hydroxyhydantoin nucleosides to undergo isomerization may complicate the biological processing of this damage in cellular DNA.
    No preview · Article · Nov 2015 · Chemical Research in Toxicology
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    ABSTRACT: Attrition due to nonclinical safety represents a major issue for the productivity of pharmaceutical research and development (R&D) organizations, especially during the compound optimization stages of drug discovery and the early stages of clinical development. Focusing on decreasing nonclinical safety-related attrition is not a new concept and various approaches have been experimented over the last two decades. Front-loading testing funnels in Discovery with in vitro toxicity assays designed to rapidly identify unfavorable molecules was the approach adopted by most pharmaceutical R&D organizations a few years ago. However, this approach has also a non-negligible opportunity cost. Hence, significant refinements to the "fail early, fail often" paradigm have been proposed recently to reflect the complexity of accurately categorizing compounds with early data points without taking into account other important contextual aspects, in particular efficacious systemic and tissue exposures. This review provides an overview of toxicology approaches and models that can be used in pharmaceutical Discovery at the series/lead identification and lead optimization stages to guide and inform chemistry efforts, as well as a personal view on how to best use them to meet nonclinical safety-related attrition objectives consistent with a sustainable pharmaceutical R&D model. The scope of this review is limited to small molecules, as large molecules are associated with challenges that are quite different. Finally, a perspective on how several emerging technologies may impact toxicity evaluation is also provided.
    No preview · Article · Nov 2015 · Chemical Research in Toxicology
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    ABSTRACT: Arsenic is the most ubiquitous environmental toxin and carcinogen. Long-term exposure to arsenic is associated with human diseases including cancer, cardiovascular disease and diabetes. Human As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT) methylates As(III) to trivalent mono- and dimethyl species that are more toxic and potentially more carcinogenic than inorganic arsenic. Modulators of hAS3MT activity may be useful for prevention or treatment of arsenic-related diseases. Using a newly developed high-throughput assay for hAS3MT activity, we identified ten novel noncompetitive small molecule inhibitors. In silico docking analysis with the crystal structure of an AS3MT ortholog suggests that the inhibitors bind in a cleft between domains that is distant from either the As(III) or SAM binding sites. This suggests the presence of a possible allosteric and regulatory site in the enzyme. These inhibitors may be useful tools for future research in arsenic metabolism and are the starting-point for development of drugs against hAS3MT.
    Preview · Article · Nov 2015 · Chemical Research in Toxicology
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    ABSTRACT: Prolonged exposure to aristolochic acid (AA) contaminated slimming drugs and food is believed to be associated with the development of endemic nephropathy in Belgian women and in farmers living alongside the Danube River. Decades of research have revealed the pathophysiology of carcinogenesis of AA, the molecular mechanisms underlying renal interstitial fibrosis remain unclear. We hypothesized RNA modification may have contributed to the observed toxicity of AA. Thus, a highly sensitive and selective ultra-performance liquid chromatography-coupled tandem mass spectrometric method was developed to quantify RNA-AA adducts in target and non-target organs of AA-dosed rats. The results revealed, for the first time, that AA form RNA adducts in vitro and in vivo. Comparative studies on DNA revealed that RNA is modified by AA at frequencies approximately 6-fold higher than that of DNA in both kidney and liver tissue in AA-dosed rats. Results also demonstrated that guanosine is modified by AA at frequencies significantly higher than that of adenosine, 2-deoxyadenosine, and 2-deoxyguanosine in both organs of the AA-dosed. This finding suggests that guanosine is a major target for AA and that guanosine adducts of AA might be critical lesions in the pathophysiology of AA-induced toxicity. It is anticipated that the results of our study may open up a new area of investigating the nephrotoxicity and/or carcinogenicity by quantifying RNA adducts using UPLC-MS/MS technique of high sensitivity and selectivity.
    No preview · Article · Jan 2015 · Chemical Research in Toxicology