Journal of Applied Toxicology

Cover image for Vol. 33 Issue 8

August 2013

Volume 33, Issue 8

Pages 700–860

  1. Review Article

    1. Top of page
    2. Review Article
    3. Research Articles
    1. Toxicity of ethylmercury (and Thimerosal): a comparison with methylmercury (pages 700–711)

      José G. Dórea, Marcelo Farina and João B. T. Rocha

      Version of Record online: 11 FEB 2013 | DOI: 10.1002/jat.2855

      EtHg toxicity differs from that of meHg, leading to different toxicity risks. In vitro studies comparing etHg with meHg demonstrate equivalent measured outcomes for cardiovascular, neural, and immune cells. However, distinct toxicokinetic profile between meHg and etHg, results in different compartmental distribution and shorter blood half-life for etHg which can be explained by a faster in vivo dealkylation of etHg than meHg. Immunotoxicity is more pronounced and more common for thimerosal etHg.

  2. Research Articles

    1. Top of page
    2. Review Article
    3. Research Articles
    1. Cytotoxicity of dioscin in human gastric carcinoma cells through death receptor and mitochondrial pathways (pages 712–722)

      Mingming Hu, Lina Xu, Lianhong Yin, Yan Qi, Hua Li, Youwei Xu, Xu Han, Jinyong Peng and Xianyao Wan

      Version of Record online: 14 FEB 2012 | DOI: 10.1002/jat.2715

      In this study, Table 1 shows the information of primer, anneal temperature and cycle of RT-PCR. PCR of all genes was performed under the conditions in this table. β-Actin was chosen as house-keeping gene. Table 2 is the results of apoptosis assay by flow cytometry. In the presence of dioscin, the rate of early apoptosis, advanced stage apoptosis and necrosis of cancer cells was increased in a dose-dependent manner.

    2. Slow delayed rectifying potassium current (IKs) – analysis of the in vitro inhibition data and predictive model development (pages 723–739)

      Sebastian Polak, Barbara Wiśniowska, Anna Glinka, Kamil Fijorek and Aleksander Mendyk

      Version of Record online: 14 FEB 2012 | DOI: 10.1002/jat.2719

      The IKr (hERG) current inhibition is considered to be the main target during the drug development process, although other ionic currents modification can either potentiate or mask hERG channel blockade. Database describing the results of in vitro studies investigating the chemical-IKs current interactions has been developed. Based on the collected data the predictive extended-QSAR models for the IC50 estimation were developed with the use of various algorithms. The best performing model was further built into the ToxComp platform (ToxIVIVE).

    3. Chromatographic determination of drugs of abuse in vitreous humor using solid-phase extraction (pages 740–745)

      Purificación Fernández, Santiago Seoane, Cristina Vázquez, María Jesús Tabernero, Antonia M. Carro and Rosa A. Lorenzo

      Version of Record online: 15 FEB 2012 | DOI: 10.1002/jat.2722

      A method is presented for the determination of drugs of abuse in vitreous humor using high-performance liquid chromatography and solid-phase extraction. A linear response from the detector was obtained within the concentration range of 0.1–4 µg mL−1, the limits of detection were lower than 30 ng mL−1, the coefficients of variation fluctuated between 0.1% and 12.4%, and the average recoveries were >78% for all the drugs except for EDDP, with a value of 66.4%.

    4. Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells (pages 756–765)

      Jianteng Wei, Ming Liu, Haizhou Liu, Hui Wang, Fengxia Wang, Yuyan Zhang, Lijun Han and Xiukun Lin

      Version of Record online: 8 JUN 2012 | DOI: 10.1002/jat.2725

      Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits potential anti-tumor activity against many tumor cell lines. This study aims to examine the anti-tumor activity of OA on pancreatic cancer cells and its potential molecular mechanism. The results showed that the proliferation of Panc-28 cells was inhibited by OA in a concentration-dependent manner, with an IC50 (The half maximal inhibitory concentration) value of 46.35 µg ml−1, as determined by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.

    5. LOSS of Mrp1 alters detoxification enzyme expression in a tissue- and hormonal-status-specific manner (pages 766–773)

      Jeffrey C. Sivils, Tiffany M. Ancrum and Lisa J. Bain

      Version of Record online: 23 APR 2012 | DOI: 10.1002/jat.2727

      In mice lacking Mrp1, renal phase II and III enzyme expression was significantly changed owing to the loss of androgens, while in the lungs, phase II and phase III enzymes were downregulated in Mrp1−/− mice, irrespective of their hormonal status. Expression in the small intestine was only different between intact and castrated Mrp1−/− mice, and not different in wildtype FVB mice. Enzyme expression patterns correlated to Nrf2 expression. This information will aid in the understanding of how drug uptake, disposition and elimination can be influenced by both hormone status and the presence and magnitude of transporter expression.

    6. Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice (pages 774–783)

      Mohamed A. Hammad, Mohamed Sadek Abdel-Bakky, Larry A. Walker and Mohammad K. Ashfaq

      Version of Record online: 9 MAR 2012 | DOI: 10.1002/jat.2728

      Tissue factor (TF) is a membranous glycoprotein that functions as a receptor for coagulation factor VII/VIIa and activates the coagulation system when blood vessels or tissues are damaged. TF was upregulated in our monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity model. We tested the hypothesis that TF-dependent fibrin deposition and lipid peroxidation in the form of oxidized low-density-lipoprotein (ox-LDL) accumulation contribute to liver inflammation induced by MCT/LPS in mice. In the present study, we blocked TF using antisense oligodeoxynucleotides against mouse TF (TF-ASO).

    7. Ethanol consumption modifies the body turnover of cadmium: a study in a rat model of human exposure (pages 784–798)

      Malgorzata M. Brzóska, Malgorzata Galażyn-Sidorczuk and Ilona Dzwilewska

      Version of Record online: 8 MAR 2012 | DOI: 10.1002/jat.2734

      The impact of ethanol on the body turnover of cadmium in a rat model reflecting excessive alcohol consumption in humans chronically exposed to moderate and relatively high levels of this heavy metal was studied. The results provide strong evidence that ethanol consumption under long-term moderate and relatively high exposure to cadmium modifies its metabolism in the organism, resulting in lower body burden of this toxic metal. Based on the findings, it can be concluded that cadmium concentration in the blood and tissues of alcohol abusers chronically exposed to moderate and relatively high levels of this metal may be lower, whereas its urinary excretion is higher than in their non-drinking counterparts. However, since ethanol is toxic itself, the decreased body burden of cadmium owing to alcohol consumption does not allow for the conclusion that the risk of health damage may be lower with co-exposure to these xenobiotics. In further study, it will be investigated how the ethanol-induced changes in the body status of cadmium influence the effects of its toxic action.

    8. Apoptotic responses of zebrafish (Danio rerio) after exposure with microcystin-LR under different ambient temperatures (pages 799–806)

      Wei Ji, Hualei Liang, Wenshan Zhou and Xuezhen Zhang

      Version of Record online: 9 MAR 2012 | DOI: 10.1002/jat.2735

      Microcystins (MCs) can cause evident hepatic apoptosis. In vitro studies indicated that uptake of MC by isolated hepatocytes was dramatically reduced as ambient temperature dropped, and some studies presented a hypothesis that differences in core body temperatures in animals result in diverse uptake of MC, as well as different toxic effects. Thus far, however, few in vivo studies have been conducted to investigate the effects of temperature on MC-induced hepatocyte apoptosis in fish, a typical poikilotherm.

    9. Gene expression profiling reveals potential key pathways involved in pyrazinamide-mediated hepatotoxicity in Wistar rats (pages 807–819)

      Yun Zhang, Zhenzhou Jiang, Yijing Su, Mi Chen, Fu Li, Li Liu, Lixin Sun, Yun Wang, Shuang Zhang and Luyong Zhang

      Version of Record online: 19 MAR 2012 | DOI: 10.1002/jat.2736

      Pyrazinamide (PZA) is an important sterilizing prodrug that shortens the duration of tuberculosis therapy. However, hepatotoxicity has been reported during clinical trials investigating PZA. To determine the hepatotoxic effects of PZA in vivo and to further investigate the underlying cellular mechanism, we profiled the gene expression patterns of PZA-treated rat livers by microarray analysis. Wistar rats of both sexes were orally administered PZA at doses of 0.5, 1.0 and 2.0 g kg−1 for 28 days.

    10. Methyl tert butyl ether is anti-angiogenic in both in vitro and in vivo mammalian model systems (pages 820–827)

      John Kozlosky, Josephine Bonventre and Keith Cooper

      Version of Record online: 8 MAR 2012 | DOI: 10.1002/jat.2737

      Methyl-tertiary butyl ether (MTBE) was shown to be anti-angiogenic in zebrafish, mice implanted with an ECGS fortified Matrigel plug and interfered with rat brain endothelial cells microcapillary tube formation. MTBE (500–1500 mg/kg) did not cause any growth or histological malformations in Fisher 344 dams or pups. MTBE is antiagiogenic, minimally toxic and possibly could be used to treat solid tumors.

    11. Geraniol inhibits murine skin tumorigenesis by modulating COX-2 expression, Ras-ERK1/2 signaling pathway and apoptosis (pages 828–837)

      Sandeep Chand Chaudhary, Mohammad Saeed Siddiqui, Mohammad Athar and Mohammad Sarwar Alam

      Version of Record online: 4 JUL 2012 | DOI: 10.1002/jat.2739

      The chemopreventive effect of geraniol was investigated against 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-mediated skin tumorigenesis in female Swiss albino mice. Effects of geraniol on TPA-induced skin edema, hyperplasia, COX-2, oxidative stress, ornithine decarboxylase and [3H] thymidine incorporation were observed. We studied geraniol treatment on incidence and number of tumor and on the expressions of Ras, Raf, ERK1/2, Bcl2 and Bax proteins in skin tumors. Our study concludes that Geraniol alters Ras proliferation pathway and pro-apoptotic state to inhibit DMBA/TPA-mediated skin tumorigenesis.

    12. Hair testing for cocaine and metabolites by GC/MS: criteria to quantitatively assess cocaine use (pages 838–844)

      O. López-Guarnido, I. Álvarez, F. Gil, L. Rodrigo, H. C. Cataño, A. M. Bermejo, M. J. Tabernero, A. Pla and A. F. Hernández

      Version of Record online: 9 MAR 2012 | DOI: 10.1002/jat.2741

      A simple, rapid and sensitive GC/MS method has been developed and validated for the sensitive determination of cocaine and its main metabolites cocaethylene and benzoylecgonine in hair. The method is reproducible, robust and precise and fully satisfactory for its application to routine laboratory testing. The procedure was further applied to 40 hair samples from self-reported cocaine users. A new criterion was raised that contributes to minimize false-negative results and allows for a better interpretation of hair testing results.

    13. CCR5 plays an important role in resolving an inflammatory response to single-walled carbon nanotubes (pages 845–853)

      Eun-Jung Park, Jinkyu Roh, Soo Nam Kim, Younghun Kim, Sang-Bae Han and Jin Tae Hong

      Version of Record online: 22 MAR 2012 | DOI: 10.1002/jat.2744

      Owing to the development of new materials and technology, the pollutants in the environment are becoming more varied and complex over time. In our previous study using ICR mice, we suggested that a single intratracheal instillation of single-walled carbon nanotubes (SWCNTs) induced early lung fibrosis and subchronic tissue damage. In the present study, to investigate the role of CCR5 in inflammatory responses to the uptake of SWCNTs, we compared BAL (Bronchoalveolar lavage) cell composition, cell cycles, cytokines, cell phenotypes, inflammatory response-related proteins, cell surface receptors and histopathology using CCR5 knockout (KO) and wild-type mice.

    14. In vivo protective effect of Copaifera langsdorffii hydroalcoholic extract on micronuclei induction by doxorubicin (pages 854–860)

      Jacqueline Morais Alves, Carla Carolina Munari, Moacir de Azevedo Bentes Monteiro Neto, Ricardo Andrade Furtado, Juliana Marques Senedese, Jairo Kenupp Bastos and Denise Crispim Tavares

      Version of Record online: 19 MAY 2012 | DOI: 10.1002/jat.2777

      The present study was undertaken to evaluate the genotoxic potential of Copaifera langsdorffii leaf hydroalcoholic extract (CLE) and its influence on the genotoxicity induced by the chemotherapeutic agent doxorubicin (DXR) using the Swiss mouse peripheral blood micronucleus test. The results demonstrated that CLE itself was not genotoxic. In animals treated with CLE and DXR, the number of micronucleus was significantly decreased compared to animals receiving DXR alone.

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