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Research ArticleArticle

Evaluation of Hepatic Glutathione Transferase Mu 1 and Theta 1 Activities in Humans and Mice Using Genotype Information

Shingo Arakawa, Kazunori Fujimoto, Ayako Kato, Seiko Endo, Aiko Fukahori, Akira Shinagawa, Thomas Fischer, Juergen Mueller and Wataru Takasaki
Drug Metabolism and Disposition March 2012, 40 (3) 497-503; DOI: https://doi.org/10.1124/dmd.111.042911
Shingo Arakawa
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Kazunori Fujimoto
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Ayako Kato
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Seiko Endo
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Aiko Fukahori
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Akira Shinagawa
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Thomas Fischer
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Juergen Mueller
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Wataru Takasaki
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Abstract

We investigated the impact of glutathione transferases Mu 1 (GSTM1)- and glutathione transferase Theta 1 (GSTT1)-null genotypes on hepatic GST activities in humans and compared the results with those of Gstm1- and Gstt1-null mice. In liver with GSTM1/Gstm1-null genotype, GST activity toward p-nitrobenzyl chloride (NBC) was significantly decreased in both humans and mice. In addition, in liver with GSTT1/Gstt1-null genotype, GST activity toward dichloromethane (DCM) was significantly decreased in both humans and mice. Therefore, null genotypes of GSTM1/Gstm1 and GSTT1/Gstt1 are considered to decrease hepatic GST activities toward NBC and DCM, respectively, in both humans and mice. This observation shows the functional similarity between humans and mice for GSTM1 and GSTT1 toward some substrates. In the case of NBC and DCM, Gst-null mice would be relevant models for humans with GST-null genotype. In addition, decreases in GST activities toward 1,2-dichloro-4-nitrobenzene, trans-4-phenyl-3-buten-2-one, and 1-chloro-2,4,-dinitrobenzene were observed in Gstm1-null mice, and a decrease in GST activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was observed in Gstt1-null mice. However, an impact of GST-null genotypes on GST activities toward these substrates was not observed in humans. In the case of these mouse-specific substrates, Gst-null mice may be relevant models for humans regardless of GST genotype, because GST activities, which are higher in wild-type mice than in humans, were eliminated in Gst-null mice. This study shows that comparison of hepatic GST activities between humans and mice using genotype information would be valuable in using Gst-null mice as human models.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.042911.

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

  • ABBREVIATIONS:

    GST
    glutathione transferase
    GSTM1
    glutathione transferase Mu 1
    GSTT1
    glutathione transferase Theta 1
    DILI
    drug-induced liver injury
    NBC
    p-nitrobenzyl chloride
    DCM
    dichloromethane
    CDNB
    1-chloro-2,4,-dinitrobenzene
    DCNB
    1,2-dichloro-4-nitrobenzene
    PBO
    trans-4-phenyl-3-buten-2-one
    EPNP
    1,2-epoxy-3-(p-nitrophenoxy)propane
    ADME
    absorption, distribution, metabolism, excretion.

  • Received September 22, 2011.
  • Accepted December 14, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

GST-NULL GENOTYPES AND HEPATIC ACTIVITIES IN HUMANS AND MICE

Shingo Arakawa, Kazunori Fujimoto, Ayako Kato, Seiko Endo, Aiko Fukahori, Akira Shinagawa, Thomas Fischer, Juergen Mueller and Wataru Takasaki
Drug Metabolism and Disposition March 1, 2012, 40 (3) 497-503; DOI: https://doi.org/10.1124/dmd.111.042911

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Research ArticleArticle

GST-NULL GENOTYPES AND HEPATIC ACTIVITIES IN HUMANS AND MICE

Shingo Arakawa, Kazunori Fujimoto, Ayako Kato, Seiko Endo, Aiko Fukahori, Akira Shinagawa, Thomas Fischer, Juergen Mueller and Wataru Takasaki
Drug Metabolism and Disposition March 1, 2012, 40 (3) 497-503; DOI: https://doi.org/10.1124/dmd.111.042911
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