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Drug Metabolism and Disposition Fast Forward
First published on June 7, 2006; DOI: 10.1124/dmd.106.010009

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Received for publication March 7, 2006.
Revised June 4, 2006.
Accepted for publication June 5, 2006.

Characterization of phenotypes in Gstm1-null mice by cytosolic and in vivo metabolic study using DCNB

Kazunori Fujimoto 1*, Shingo Arakawa 1, Yukari Shibaya 1, Hiroaki Miida 1, Yosuke Ando 1, Hiroaki Yasumo 1, Ayako Hara 1, Minoru Uchiyama 1, Haruo Iwabuchi 1, Wataru Takasaki 1, Sunao Manabe 1, Takashi Yamoto 1

1 Sankyo Co., Ltd.

* Address correspondence to: E-mail: kazunf{at}sankyo.co.jp

Abstract

Glutathione S-transferase Mu 1 (GSTM1) has been regarded as one of the key enzymes involved in phase II reactions in the liver, due to its high expression level. In this study, we generated mice with disrupted glutathione S-transferase Mu 1 gene (Gstm1-null mice) by gene targeting, and characterized the phenotypes by cytosolic and in vivo studies. The resulting Gstm1-null mice appeared to be normal and were fertile. Expression analyses for the Gstm1-null mice revealed a deletion of Gstm1 mRNA and a small decrease in Gsta3 mRNA. In the enzymatic study, GST activities toward 1,2-dichloro-4-nitrobenzene (DCNB) and 1-chloro-2,4-dinitrobenzene (CDNB) in the liver and kidney cytosols were markedly lower in Gstm1-null mice than in the wild-type control. Gstm1-null mice had GST activities of only 6.1-21.0% of the wild-type control to DCNB and 26.0-78.6% of the wild-type control to CDNB. After a single oral administration of DCNB to Gstm1-null mice, the plasma concentration of DCNB showed larger AUC0-24 (5.1-5.3 times, vs. the wild-type control) and higher Cmax (2.1-2.2 times, vs. the wild-type control) with a correspondingly lower level of GSH-related metabolite (AUC0-24: 9.4-17.9% and Cmax: 9.7-15.6% of the wild-type control). In conclusion, Gstm1-null mice showed markedly low ability of glutathione conjugation to DCNB in the cytosol and in vivo and would be useful as a deficient model of GSTM1 for ADME/Tox studies.


Key words: genomics, glutathione transferases, pharmacokinetics, toxicokinetics


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Home page
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K. Fujimoto, S. Arakawa, T. Watanabe, H. Yasumo, Y. Ando, W. Takasaki, S. Manabe, T. Yamoto, and S.-i. Oda
Generation and Functional Characterization of Mice with a Disrupted Glutathione S-Transferase, Theta 1 Gene
Drug Metab. Dispos., December 1, 2007; 35(12): 2196 - 2202.
[Abstract] [Full Text] [PDF]


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