Fundamental Toxicological Sciences
Online ISSN : 2189-115X
ISSN-L : 2189-115X
Volume 3, Issue 3
Displaying 1-7 of 7 articles from this issue
Letter
  • Tetsuro Araki, Norihiko Iwazaki, Naoki Ishiguro, Atsushi Sakamoto, Kei ...
    2016 Volume 3 Issue 3 Pages 89-99
    Published: April 05, 2016
    Released on J-STAGE: April 05, 2016
    JOURNAL FREE ACCESS
    Supplementary material
    Predicting drug-induced liver injury is still a big challenge for the research and development of pharmaceuticals. Primary human hepatocytes (PHH) are the gold standard cell sources for examining drug metabolism, drug-drug interaction (DDI) and hepatotoxicity in humans in vitro. However, their supply does not meet the demand of laboratories sufficiently, and only a limited number of lots of PHH are commercially available. Recently, human iPS cell-derived hepatocytes have been reported and are anticipated to be used as an alternative to PHH. However, drug metabolizing activities of these human iPS-derived hepatocytes have not been well characterized and quantitative target values for PHH alternatives remain unknown. In this study, we collected 179 data sheets of commercially available PHH lots from 4 vendors to clarify the characteristics of PHH in drug metabolism and DDI. We identified the most frequently observed value ranges (MFRs) of the activities of major drug metabolizing enzymes (CYP3A4/5, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT, and SULT) and drug transporters. Moreover, we also identified MFRs of fold changes of CYP inductions by each typical inducer both in the mRNA levels and the enzyme activity levels of CYP1A2, CYP2B6, and CYP3A. We suggest that these MFRs are the first milestone to develop and evaluate human iPS cell-derived hepatocytes as alternatives to PHH in pharmaceutical research for assessing absorption, distribution, metabolism, excretion, and toxicity.
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Original Article
  • Masami Ishido, Eiko Shimaya
    2016 Volume 3 Issue 3 Pages 101-108
    Published: April 20, 2016
    Released on J-STAGE: April 20, 2016
    JOURNAL FREE ACCESS
    Animal models can help determine the etiology of neurodegenerative diseases such as Parkinson’s disease. Here, we conducted transcriptome analysis of the rotenone model of Parkinson’s disease in rats. Exposure of 9-week-old Wistar rats to rotenone at 3 mg/kg/day for 14 days reduced spontaneous motor activity to 49% of that of control rats. Immunohistochemical analysis revealed increased expression of major histocompatibility complex (MHC) molecules in the substantia nigra of rotenone-treated rats, which was deduced by DNA array analysis. Further, gene set enrichment analysis of the transcriptome extracted the presence of a cytokine network, which included TNF-α. The expression of these proteins tended to be reduced at developed states of the disease. Thus, our analyses of the rotenone rat model still provides new insights into the etiology of Parkinson’s disease.
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Letter
  • Takato Hara, Hiroka Matsuzaki, Takehiro Nakamura, Eiko Yoshida, Takano ...
    2016 Volume 3 Issue 3 Pages 109-113
    Published: May 11, 2016
    Released on J-STAGE: May 11, 2016
    JOURNAL FREE ACCESS
    Organic-inorganic hybrid molecules, which have organic structure and metal atoms, can exhibit various biological activities that are distinctly different from their components. Consequently, organic-inorganic hybrid molecules are considered an effective tool to analyze biological systems. Herein, we investigated the cytotoxicity of zinc, copper, and rhodium complexes, with either 1,10-phenanthroline or 2,9-dimethyl-1,10-phenanthroline as a common ligand, in cultured vascular endothelial cells. The copper complexes, that is, dichloro(1,10-phenanthroline) copper and dichloro(2,9-dimethyl-1,10-phenanthroline) copper, exhibited high cytotoxicity accompanied by considerable accumulation inside the cells. Potassium tetrachloro(1,10-phenanthroline) rhodate also exhibited cytotoxicity and considerable accumulation. Thus, it was found that the cytotoxicity of organic-inorganic hybrid molecules to vascular endothelial cells depends on the interaction between the intramolecular metal and ligand, which facilitates their uptake by the cells.
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Letter
  • Shuso Takeda, Shunsuke Okajima, Momoko Noguchi, Hiroko Miyoshi, Kuniyo ...
    2016 Volume 3 Issue 3 Pages 115-119
    Published: May 11, 2016
    Released on J-STAGE: May 11, 2016
    JOURNAL FREE ACCESS
    Cancer cells can develop resistance to anti-cancer agents. Although some mechanisms have been suggested for this resistance to treatments, further detailed research is required. Historically, sesquiterpene lactones (SLs) have been shown to exhibit toxicity in humans and animals due to their chemical nature. Among the SLs identified to date, (–)-xanthatin, which was originally obtained in an extract from Xanthium strumarium, is reportedly less toxic to animals. Furthermore, accumulating evidence suggests that some SLs can kill cancer cells. Therefore, we have focused on (–)-xanthatin and established a method for the chemical synthesis of SLs in order to obtain a pure form. Although we showed that (–)-xanthatin exerts anti-proliferative effects on highly aggressive (poorly differentiated) human MDA-MB-231 breast cancer cells via a mechanism involving the induction of GADD45γ, a tumor suppressor gene, other molecular target(s) of the molecule have not yet been identified. In the present study, we employed chemically synthesized pure (–)-xanthatin to investigate the targets involved in (–)-xanthatin-mediated cell death. The results obtained revealed marked increases in FosB, the expression of which is suggested to be down-regulated in poorly differentiated breast cancers, and the stimulated expression of FosB as well as cell death by (–)-xanthatin was abrogated by N-acetyl-L-cysteine (a ROS-scavenging agent). The possible participation of FosB in (–)-xanthatin-evoked cell death is discussed.
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Letter
  • Hiromitsu Tsuzuki, Shota Inoue, Daiki Kobayashi, Gantulga Uuganbaatar, ...
    2016 Volume 3 Issue 3 Pages 121-125
    Published: May 11, 2016
    Released on J-STAGE: May 11, 2016
    JOURNAL FREE ACCESS
    Methyl cinnamate (MC) and essential oils containing MC possess beneficial antimicrobial, antifungal, and insecticidal effects, among others. Such effects are related to the biocidal action of MC. The antioxidant activity of MC has also been reported elsewhere. It has been suggested that MC may be cytotoxic to cells exposed to oxidative stress. To test this possibility, the effect of MC on rat thymocytes was examined while the cells were subjected to oxidative stress induced by hydrogen peroxide (H2O2). Flow cytometric techniques with appropriate fluorescent probes were used for quantification. MC increased cell vulnerability to oxidative stress via acceleration of the cell death process and/or potentiation of oxidative stress. The use of MC is widespread because of its beneficial actions, and thus further attention should be paid to whether MC is effective under oxidative stress.
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Letter
  • Jinfeng Liang, Wangdong Jin, Haibin Wei, Hongwen Li, Fei Jia, Jing Qia ...
    2016 Volume 3 Issue 3 Pages 127-135
    Published: May 11, 2016
    Released on J-STAGE: May 11, 2016
    JOURNAL FREE ACCESS
    Quetiapine fumarate (QF) is a widely used antipsychotic agent for the first-line treatment of schizophrenia, with good tolerability and compliance in humans and no observed adverse effects against liver. Taking advantages of zebrafish, which can be utilized in rapid drug screening and acute toxicity assessment, our study determined a certain hepatotoxicity of QF for the first time, indicating a potential safety hazard of this commonly used drug to humans.
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Original Article
  • Hidehiko Kikuchi, Futoshi Kuribayashi, Hitomi Mimuro, Shinobu Imajoh-O ...
    2016 Volume 3 Issue 3 Pages 137-142
    Published: May 17, 2016
    Released on J-STAGE: May 17, 2016
    JOURNAL FREE ACCESS
    Supplementary material
    A typical DNA-damaging agent 4-nitroquinoline 1-oxide (4NQO) is known as an experimental oral carcinogen. Although 4NQO was initially characterized as a UV-mimetic agent, it shows more complex effects inducing production of various covalent adducts, oxidative damage and DNA single strand break in DNA. To understand roles of histone acetyltransferase GCN5, which protects cells against UV-irradiation, on repair of 4NQO-induced DNA damage, we studied the sensitivity of chicken homozygous DT40 mutants, ∆GCN5, against 4NQO. After 4NQO treatment, the viability of ∆GCN5 was appreciably reduced (to ~25% at 6 hr) as compared to that of wild type DT40. Semiquantitative RT-PCR showed that transcription of DNA polymerase η (POLH) gene whose deficiency is responsible for a variant form of xeroderma pigmentosum was drastically down-regulated in ∆GCN5 (to ~25%). However, overexpression of POLH could not rescue ∆GCN5 from the enhanced sensitivity to 4NQO, unlike UV-irradiation. Our data suggested that GCN5 participates in control of the sensitivity against 4NQO, and the molecular mechanisms of GCN5-mediated repair of the 4NQO-induced DNA lesions are highly complex.
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