Journal of Applied Toxicology

Cover image for Vol. 32 Issue 12

December 2012

Volume 32, Issue 12

Pages 945–1020

  1. Review Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. Tyrosine kinase inhibitor (TKI)-induced cardiotoxicity: approaches to narrow the gaps between preclinical safety evaluation and clinical outcome (pages 945–951)

      Baichun Yang and Thomas Papoian

      Article first published online: 10 SEP 2012 | DOI: 10.1002/jat.2813

      Tyrosine kinase inhibitors (TKI)-induced cardiac toxicity in cancer patients was not well predicted by preclinical studies, owing to the lack of a comprehensive TKI mechanism of action and appropriate cardiac functional evaluation. To help close the gaps, additional preclinical testing is proposed, including: precise determination of the mechanism of action, cardiomyocyte cultures for screening potentially cardiotoxic drugs, functional assessments using isolated perfused heart methodology or echocardiography, and assessment of both safety and efficacy in animal models of disease.

    2. Health effects of extremely low-frequency magnetic fields: reconsidering the melatonin hypothesis in the light of current data on magnetoreception (pages 952–958)

      Jacques Vanderstraeten, Luc Verschaeve, Hynek Burda, Catherine Bouland and Christophe de Brouwer

      Article first published online: 13 JUN 2012 | DOI: 10.1002/jat.2761

      Most studies on the melatonin (MLT) hypothesis in rats have reported partial inhibition of MLT secretion under long term exposure to weak ELF magnetic fields (MF). Recent data on magnetoreception and on cancer promotion by circadian disruption encourage to go back to the MLT hypothesis, with applying it the association between ELF MF and childhood leukemia, and with envisaging possible involvement of the magnetic sense.

  2. Research Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. Juvenile rats do not exhibit elevated sensitivity to acrylamide toxicity after oral administration for 12 weeks (pages 959–967)

      Shigeaki Takami, Toshio Imai, Young-Man Cho, Kumiko Ogawa, Masao Hirose and Akiyoshi Nishikawa

      Article first published online: 28 APR 2011 | DOI: 10.1002/jat.1686

      To clarify the general toxicity of acrylamide in the juvenile rats, acrylamide was administered to F344 rats after birth for 12 weeks. Reduction of body weight was noted in 20 and 40 ppm females. Acrylamide-induced histopathological changes were limited to degeneration and necrosis of the seminiferous epithelium in the testes and desquamated epithelium in the epididymides in 40 ppm males. Taken together with previous reports, juvenile rats are not necessarily more susceptible to acrylamide-induced toxicity as compared with young adults.

    2. Commercial naphthenic acids and the organic fraction of oil sands process water induce different effects on pro-inflammatory gene expression and macrophage phagocytosis in mice (pages 968–979)

      Erick Garcia-Garcia, Jonathan Pun, Jordan Hodgkinson, Leonidas A. Perez-Estrada, Mohamed Gamal El-Din, Daniel W. Smith, Jonathan W. Martin and Miodrag Belosevic

      Article first published online: 24 MAY 2011 | DOI: 10.1002/jat.1687

      Naphthenic acids (NAs) are believed to be the major toxic component of oil sands process water (OSPW). We evaluated whether commercial NAs are an adequate model to study OSPW toxicity in complex organisms. We compared the effects of commercial NAs preparation and the organic fraction of OSPW by measuring the pro-inflammatory gene expression and macrophage phagocytosis, and found that commercial NAs and OSPW induce different biological effects in mice.

    3. N-acetyl-cysteine protects chicken growth plate chondrocytes from T-2 toxin-induced oxidative stress (pages 980–985)

      Shao-jun He, Jia-fa Hou, Yu-yi Dai, Zhen-lei Zhou and Yi-feng Deng

      Article first published online: 28 JUL 2011 | DOI: 10.1002/jat.1697

      In this study, primary cultures of chicken tibial growth plate chondrocytes were treated with T-2 toxin in the absence and presence of N-acetyl-cysteine (NAC) to investigate the effects of NAC on T-2 toxin toxicity. Our results showed that T-2 toxin-induced cytotoxicity was reversed, in part, by antioxidant NAC (P < 0.05), suggesting that T-2 toxin inhibits the proliferation and differentiation of GPCs in vitro by altering cellular homeostasis and NAC can protect GPCs against T-2 toxin cytotoxicity.

    4. Selective apoptotic effects of piceatannol and myricetin in human cancer cells (pages 986–993)

      Paloma Morales and Ana I. Haza

      Article first published online: 20 SEP 2011 | DOI: 10.1002/jat.1725

      The aim of the present study was to evaluate the apoptotic effects of piceatannol and myricetin, alone or in combination, in HL-60 (leukemia) and HepG2 (hepatoma) cells. Both polyphenols induced apoptotic cell death synergistically in HL-60 cells. However, the percentage of apoptotic HepG2 cells was only significant after piceatannol treatment and in combined treatment was even lower. Our results also indicate that apoptosis induced by piceatannol and myricetin occurs through an ROS-independent cell death pathway.

    5. Impact of six fruits—banana, guava, mangosteen, pineapple, ripe mango and ripe papaya—on murine hepatic cytochrome P450 activities (pages 994–1001)

      Waranya Chatuphonprasert and Kanokwan Jarukamjorn

      Article first published online: 13 APR 2012 | DOI: 10.1002/jat.2740

      The effects of six fruits-banana, guava, mangosteen, pineapple, ripe mango, and ripe papaya-on murine CYP1A1, CYP1A2, CYP2E1, and CYP3A11 activities were investigated. Pineapple juice showed the strongest inhibitory effect against P450s in vitro, followed by mangosteen, guava, ripe mango, ripe papaya, and banana. In vivo, the pineapple juice raised ethoxyresorufin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities, corresponded to the expression of CYP1A1, CYP2E1, and CYP3A11 mRNAs. These observations supported that these fruits were a feasible cause of food-drug interaction.

    6. Different profiles of hepatic alkoxyresorufin O-dealkylase activities in small rodents (pages 1002–1007)

      Waranya Chatuphonprasert, Papimon Rermraksakul, Latiporn Udomsuk, Thinnakorn Lao-ong and Kanokwan Jarukamjorn

      Article first published online: 18 MAY 2012 | DOI: 10.1002/jat.2756

      Hepatic ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), pentoxyresorufin O-dealkylase (PROD) and benzyloxyresorufin O-dealkylase (BROD) enzyme activities were determined in ICR, C57BL/6, and DBA/2 mice; Sprague Dawley and Wistar rats; and Dunkin Hartley guinea pigs using β-naphthoflavone, dexamethasone and phenobarbital as inducers. Maximal induction of EROD, MROD, PROD and BROD activities were found in different strains with different inducers. These observations suggested that the choice of experimental animal strain, species and inducer is of critical importance for studies of drug metabolism and interaction.

    7. A tyrosine kinase inhibitor-induced myocardial degeneration in rats through off-target phosphodiesterase inhibition (pages 1008–1020)

      Wenyue Hu, Brad Hirakawa, Bart Jessen, Michelle Lee and Shirley Aguirre

      Article first published online: 31 AUG 2012 | DOI: 10.1002/jat.2801

      PF-04254644, a HGFR/c-MET inhibitor with off-target PDE inhibition, caused cardiomyopathy and sustained increased in heart rate in rats. Investigative studies identified PDEs inhibition, activation of c-AMP signaling, followed by intracellular calcium and oxidative stress signaling pathways as potential mechanisms of cardiac changes. Our studies substantiate the off-target mechanisms involved in the toxic effects of PF-04254644.

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