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Research ArticleArticle

Methemoglobinemia Induced by 1,2-Dichloro-4-nitrobenzene in Mice with a Disrupted Glutathione S-Transferase Mu 1 Gene

Shingo Arakawa, Takanori Maejima, Naoki Kiyosawa, Takashi Yamaguchi, Yukari Shibaya, Yoshie Aida, Ryota Kawai, Kazunori Fujimoto, Sunao Manabe and Wataru Takasaki
Drug Metabolism and Disposition September 2010, 38 (9) 1545-1552; DOI: https://doi.org/10.1124/dmd.110.033597
Shingo Arakawa
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Takanori Maejima
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Naoki Kiyosawa
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Takashi Yamaguchi
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Yukari Shibaya
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Yoshie Aida
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Ryota Kawai
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Kazunori Fujimoto
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Sunao Manabe
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Wataru Takasaki
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Abstract

A specific substrate to Mu class glutathione S-transferase (GST), 1,2-dichloro-4-nitrobenzene (DCNB), was administered to mice with a disrupted GST Mu 1 gene (Gstm1-null mice) to investigate the in vivo role of murine Gstm1 in toxicological responses to DCNB. A single oral administration of DCNB at doses of 500 and 1000 mg/kg demonstrated a marked increase in blood methemoglobin (MetHB) in Gstm1-null mice but not in wild-type mice. Therefore, Gstm1-null mice were considered to be more predisposed to methemoglobinemia induced by a single dosing of DCNB. In contrast, 14-day repeated-dose studies of DCNB at doses up to 600 mg/kg demonstrated a marked increase in blood MetHB in both wild-type and Gstm1-null mice. However, marked increases in the blood reticulocyte count, relative spleen weight, and extramedullary hematopoiesis in the spleen were observed in Gstm1-null mice compared with wild-type mice. In addition, microarray and quantitative reverse transcription-polymerase chain reaction analyses in the spleen showed exclusive up-regulation of hematopoiesis-related genes in Gstm1-null mice. These changes were considered to be adaptive responses to methemoglobinemia and attenuated the higher predisposition to methemoglobinemia observed in Gstm1-null mice in the single-dose study. In toxicokinetics monitoring, DCNB concentrations in plasma and blood cells were higher in Gstm1-null mice than those in wild-type mice, resulting from the Gstm1 disruption. In conclusion, it is suggested that the higher exposure to DCNB due to Gstm1 disruption was reflected in methemoglobinemia in the single-dose study and in adaptive responses in the 14-day repeated-dose study.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.033597.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    GST
    glutathione S-transferase
    GSTM1
    glutathione S-transferase Mu 1
    DCNB
    1,2-dichloro-4-nitrobenzene
    TK
    toxicokinetic
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    RBC
    red blood cell count
    RET
    reticulocyte count
    MetHB
    methemoglobin
    M0
    methylsulfon-N-acetyl form of 1,2-dichloro-4-nitrobenzene.

  • Received March 28, 2010.
  • Accepted June 18, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Methemoglobinemia Induced by 1,2-Dichloro-4-nitrobenzene in Mice with a Disrupted Glutathione S-Transferase Mu 1 Gene

Shingo Arakawa, Takanori Maejima, Naoki Kiyosawa, Takashi Yamaguchi, Yukari Shibaya, Yoshie Aida, Ryota Kawai, Kazunori Fujimoto, Sunao Manabe and Wataru Takasaki
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1545-1552; DOI: https://doi.org/10.1124/dmd.110.033597

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Research ArticleArticle

Methemoglobinemia Induced by 1,2-Dichloro-4-nitrobenzene in Mice with a Disrupted Glutathione S-Transferase Mu 1 Gene

Shingo Arakawa, Takanori Maejima, Naoki Kiyosawa, Takashi Yamaguchi, Yukari Shibaya, Yoshie Aida, Ryota Kawai, Kazunori Fujimoto, Sunao Manabe and Wataru Takasaki
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1545-1552; DOI: https://doi.org/10.1124/dmd.110.033597
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