Chemical Research in Toxicology Journal Impact Factor & Information

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

2015 Impact Factor Available summer 2016
2014 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

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

Publications in this journal

  • [Show abstract] [Hide abstract]
    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.
    Chemical Research in Toxicology 11/2015; DOI:10.1021/acs.chemrestox.5b00407
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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.
    Chemical Research in Toxicology 11/2015; DOI:10.1021/acs.chemrestox.5b00432
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    ABSTRACT: Poly(ADP-ribose) polymerase 1 (PARP-1) is a key eukaryotic enzyme, catalyzing the NAD+ dependent poly(ADP-ribosyl)ation of protein substrates, crucial for major DNA repair pathways, and involved in other fundamental cellular processes, such as transcription, cell cycle control, and apoptosis. Its ability to bind DNA depends on two CCHC zinc finger domains, in short, PARPzf1 and PARPzf2. Using spectroscopic methods and competitive titrations with Zn(II), Co(II) and Ni(II) ions we determined conditional dissociation constants for Zn(II) complexes of PARPzf1 and PARPzf2 at pH 7.4 (HEPES buffer), as 26 ± 4 nM and 4 ± 1 pM, respectively. The former value indicates an extremely low affinity of PARPzf1 towards metal ions, meaning that under cellular conditions PARP1zf might be largely present in a “metal-free” state. This finding provides a clue for high susceptibility of PARP-1 to oxidative stress, but also raises questions regarding activation of PARPzf1 under cellular conditions. We also determined conditional dissociation constants for Ni(II) complexes of PARPzf1 and PARPzf2 under the same conditions, as 0.78 ± 0.04 µM and 0.26 ± 0.05 nM, respectively.
    Chemical Research in Toxicology 02/2015; 28(2):191-201. DOI:10.1021/tx500320f
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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.
    Chemical Research in Toxicology 01/2015; 28(2). DOI:10.1021/tx500423m
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    ABSTRACT: The aim of the present work was to compare the antioxidative effect of the ferrocenyl-appended aurone with that of ferrocenyl-appended flavone; therefore, nine aurones together with the flavone-type analogues were synthesized by using chalcone as the reactant. The radical-scavenging property was evaluated by reacting with the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+·)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, respectively. The cytotoxicity was estimated by inhibiting 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation of DNA. It was found that the introduction of the ferrocenyl group remarkably increased the radical-scavenging activities of aurone and flavone. Especially, the ferrocenyl group in flavones can quench radicals even in the absence of the phenolic hydroxyl group, while ferrocenyl-appended aurones can efficiently protect DNA against AAPH-induced oxidation. Therefore, the antioxidative effect was generated by the ferrocenyl group and enhanced by the electron-donating group attaching to the para-position of the ferrocenyl group. Introducing the ferrocenyl group into natural compounds may be a useful strategy for increasing the antioxidative effectiveness.
    Chemical Research in Toxicology 12/2014; 28(3). DOI:10.1021/tx500405b
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    ABSTRACT: The P450-catalyzed biotransformation of the analgesic drug paracetamol (PAR) is a long-debated topic, involving different mechanistic hypotheses as well as experimental evidence for the metabolites N-acetyl-p-benzoquinone imine (NAPQI), p-benzoquinone, acetamide and 3-hydroxy-PAR. During the catalytic cycle of P450, a high-valent iron(IV)-oxo species known as Compound I (Cpd I) is formed as ultimate oxidant, featuring two energetically close-lying ground states in the doublet (low-spin) and quartet (high-spin) spin state, respectively. In order to clarify the catalytic mechanism, a computational chemistry analysis has been undertaken for both high-spin and low-spin routes, employing density functional theory (DFT) including PCM (polarized continuum-solvation model) that yields an approximate simulation of the bulk polarization exerted through the potein. The results demonstrate that hydrogen abstraction transfer (HAT) by the P450 oxidant Cpd I (FeO) is kinetically strongly preferred over the alternative pathways of an oxygen addition reaction (OAR) or two consecutive single-electron transfers (SET). Moreover, only the respective high-spin route yields N-acetyl-p-semiquinone imine (NAPSQI) as intermediate that is converted to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). By contrast, 3-hydroxy-PAR, acetamide, and p-benzoquinone as electrophilic and redox-active agent are formed predominantly in the low-spin state through reactions without involving NAPSQI. Thus all experimentally observed PAR metabolites are in accord with an initial HAT from the phenolic oxygen, and NAPSQI should indeed be the precursor of NAPQI both of which are generated only on the high-spin pathway.
    Chemical Research in Toxicology 12/2014; 28(4). DOI:10.1021/tx5003645
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    ABSTRACT: As evidenced from various in vitro and in vivo studies, metabolism of perfluorooctane sulfonate (PFOS) precursors by cytochrome P450 enzymes (CYPs) acts as an important indirect pathway for mammal PFOS exposure. Nevertheless, the mechanism of this transformation remains largely unclarified. In this study, in silico investigations adopting density functional theory (DFT) were performed to reveal the biotransformation of a typical PFOS precursor, N-ethyl perfluorooctane sulfonamide (N-EtPFOSA) catalyzed by the active species of CYPs (Compound I). Results unveil that in the enzymatic environment, N-EtPFOSA is hydroxylated feasibly (reaction energy barriers ΔE = 11.4 ~ 14.5 kcal/mol) with a H atom transfer (HAT) from the ethyl Cα to Compound I. The HAT derived Cα radical then barrierlessly combines with OH radical to produce a ferric-ethanolamine intermediate. Subsequently, the ethanolamine intermediate decomposes via N-dealkylation to perfluorooctane sulfonamide (PFOSA) and acetaldehyde products nonenzymatically with the assistance of water molecules. The rate-limiting O-addition (ΔE = 21.2 ~ 34.0 kcal/mol) of Compound I to PFOSA initiated a novel deamination pathway that comprises O-S bond formation and S-N bond cleavage. The resulting hydroxylamine is then hydrolyzed to PFOS. In addition, the results reveal that both the N-dealkylation and deamination pathways are isomeric-specific, which is consistent with experimental observations. Accordingly, DFT calculations may help uncover possible toxicological effects by predicting the biotransformation mechanisms and products of xenobiotics by CYPs.
    Chemical Research in Toxicology 12/2014; 28(3). DOI:10.1021/tx500470f
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    ABSTRACT: Nanoparticles, such as carbon nanotubes (CNTs), interact with cells and are easily internalized, causing various perturbations to cell functions. The mechanisms involved in such perturbations are investigated by a systematic approach that utilizes modified CNTs and various chemical biological assays. Three modes of actions are 1) CNTs bind to different cell surface receptors and perturb different cell signaling pathways; 2) CNTs bind to a receptor with different affinity and, therefore, strengthening or weakening signals; 3) CNTs enter cells and bind to soluble signaling proteins involved in a signaling pathway. Understanding of such mechanisms not only clarifies how CNTs cause cytotoxicity, it also demonstrates a useful method to modulate biological/toxicological activities of CNTs for their various industrial, biomedical, and consumer applications.
    Chemical Research in Toxicology 12/2014; 28(3). DOI:10.1021/tx500480d
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    ABSTRACT: In recent DNA microarray studies, we found that the transcription of Id3 gene was significantly down-regulated in five cell lines (RAW264.7, Hepa1-6, THP-1, HepG2 and HL7702) treated with two doses (50 and 100 μg/mL) of a DMSA-coated magnetite nanoparticle. Given the regulatory roles of Id genes in cell cycle, growth and differentiation, we wanted to do more investigations on effect of the nanoparticle upon the Id genes. This study detected the expression of Id genes in six cell lines (above cell lines plus HeLa) treated with the nanoparticle at the same doses using quantitative PCR. The results revealed that the expression of Id genes was significantly affected by the nanoparticle in these cell lines. Under each treatment, the Id3 gene was significantly (p<0.01) down-regulated in all cell lines, the Id1 gene was significantly down-regulated in all cell lines except the RAW264.7 cells, and the Id2 gene was significantly down-regulated in the HepG2, HL7702 and HeLa cells. Because the Id1, Id2 and Id3 genes were significantly down-regulated in three liver-derived cell lines (Hepa1-6, HepG2 and HL7702) in both microarray and PCR detections, this study then detected the expression of Id genes in the liver tissues of mice that were intravenously injected with the nanoparticle at two doses (2 and 5 mg/Kg body weight). The results revealed that the expression of Id1, Id2 and Id3 genes was also significantly down-regulated in the liver tissues under each treatment. Another Id gene, Id4, was also significantly regulated in some cells or liver tissues treated with the nanoparticle. These results reveal that the nanoparticle exerts significant effect on the in vitro and in vivo expression of Id genes. This study thus provides new insights into the Id-related nanotoxicity of the nanoparticle and the close relationship between the regulation of Id genes and iron.
    Chemical Research in Toxicology 12/2014; 28(3). DOI:10.1021/tx500333q
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    ABSTRACT: Epidemiological studies imply a significantly positive association between particulate matter (PM) level and ischemic stroke hospitalization. However, considering PM10 is highly heterogeneous and varies with season within the same location, existing experimental evidence remained to be abounded. In the present study, we first treated Wistar rats with PM10 samples collected from different seasons in Taiyuan, a typically coal-burning city of China, and determined ischemia-related markers in the cortex. The results indicated that PM10 exposure caused endothelial dysfunction, inflammatory response and neuro-functional impairment similar to that of cerebral ischemia with season-dependent properties, and winter sample presented the most obvious injuries. Then, we detected the chemical composition of PM10 samples followed by analyzing their correlation with above biomarkers, and found that winter PM10, characterized by higher polycyclic aromatic hydrocarbons (PAHs) and carbon load, played the major role for causing brain ischemia-like injuries among different season samples. Furthermore, by setting up ischemic neuron model in vitro, we confirmed that winter PM10 presented the most serious aggravation on ischemia produced injury outcome. This study provides experimental evidence for clarifying the association between season-dependent PM10 pollution in the atmospheric environment and an increased risk of ischemia-like injuries.
    Chemical Research in Toxicology 12/2014; 28(3). DOI:10.1021/tx500392n
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    ABSTRACT: The multi-kinase inhibitor sorafenib (SRF) is approved for the treatment of renal and hepatic carcinomas and is also undergoing evaluation in therapeutic combinations with other anticancer agents. SRF is generally well tolerated but produces severe toxicities in a significant proportion of patients by mechanisms that are largely unknown. It has been shown that cytochrome P450 (CYP) 3A4 has a major role in SRF biotransformation to the pharmacologically active N-oxide (SRF-Nox) and two other metabolites. In this study we prepared the major metabolites of SRF and evaluated their further biotransformation by CYPs in relation to their capacity to produce cellular toxicity. CYP3A4 was also found to be the principal enzyme that mediated the secondary oxidation of SRF metabolites. However, the reduction of SRF-Nox to SRF was also found to be a significant reaction mediated by several CYPs, especially CYPs 2B6 and 1A1. In human liver-derived HepG2 cells SRF effectively decreased ATP production to an extent greater than its metabolites. SRF also markedly altered the cell cycle distribution in HepG2 cells by decreasing the proportion in G0/G1 phase and increasing those in S- and G2/M phases. In comparison, SRF metabolites minimally affected HepG2 cell cycle progression. These findings suggest that SRF, but not its metabolites, prevents cells from entering the cell cycle and also inhibit cycling cells from completing mitosis. Reduction of the major metabolite SRF-Nox back to SRF may mediate decreased cellular viability and contribute to adverse reactions in some individuals.
    Chemical Research in Toxicology 12/2014; 28(1). DOI:10.1021/tx500373g
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    ABSTRACT: Following oral administration of empagliflozin (1000 mg/kg/day) to male and female CD-1 mice for 2 years, renal tubular injury was identified in male mice. Renal injury was not detected in male mice (≤300 mg/kg/day), in female mice (1000 mg/kg/day), or in male or female Han Wistar rats (700 mg/kg/day). Using transfected HEK293 cells and Xenopus oocytes, empagliflozin was found to be a substrate of various mouse and rat organic anion transporters (oat/Oat) and organic anion transporting polypeptide (oatp/Oatp) transporters: mouse oat3, rat Oat3, mouse oatp1a1, and rat Oatp1a1. However, using isolated kidney slices from male and female mice and rats, no sex-based difference in the extent of uptake of empagliflozin occurred. Metabolism studies using hepatic and renal microsomes from male and female mouse, rat, and human revealed a hemiacetal metabolite of empagliflozin (M466/2), predominantly formed in male mouse kidney microsomes. Formation of M466/2 in male mouse kidney microsomes was 31-fold higher compared to female mouse kidney microsomes and was ~29- and ~20-fold higher compared to male and female mouse liver microsomes, respectively. M466/2 is unstable and degrades to form a phenol metabolite (M380/1) and 4-hydroxycrotonaldehyde (4-OH CTA). Formed 4-OH CTA was trapped by reduced GSH, and the structure of the GSH adduct was confirmed by mass spectrometry. Stoichiometric formation of M380/1 from M466/2 was observed (93-96% at 24 h); however, formation of 4-OH CTA was considerably lower (~17.5% at 40 h), which is consistent with 4-OH CTA being a highly reactive species. These data represent a highly selective tissue-, species-, and sex-specific lesion in male CD-1 mice associated with a cytotoxic metabolite product, 4-OH CTA. In human, glucuronidation of empagliflozin is the most prevalent metabolic pathway and oxidation is a minor pathway. Thus, renal toxicity due to formation of 4-OH CTA from empagliflozin is not expected in humans.
    Chemical Research in Toxicology 12/2014; 28(1). DOI:10.1021/tx500380t