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Characterization of Phenotypes in Gstm1-null Mice by Cytosolic and in Vivo Metabolic Studies Using 1,2-Dichloro-4-Nitrobenzene

Medicinal Safety Research Laboratories, Sankyo Co., Ltd., Shizuoka, Japan (K.F., S.A., Y.S., H.M., Y.A., W.T., S.M., T.Y.); and Biomedical Research Laboratories (H.Y., A.H.) and Drug Metabolism and Pharmacokinetics Research Laboratories (M.U., H.I.), Sankyo Co., Ltd., Tokyo, Japan

Glutathione S-transferase Mu 1 (GSTM1) has been regarded as one of the key enzymes involved in phase II reactions in the liver, because of 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 glutathione S-transferase alpha 3 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 to 21.0% of the wild-type control to DCNB and 26.0 to 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 AUC_0–24 (5.1–5.3 times, versus the wild-type control) and higher C_max (2.1–2.2 times, versus the wild-type control), with a correspondingly lower level of glutathione-related metabolite (AUC_0–24, 9.4–17.9%; and C_max, 9.7–15.6% of the wild-type control). In conclusion, Gstm1-null mice showed markedly low ability for glutathione conjugation to DCNB in the cytosol and in vivo and would be useful as a deficient model of GSTM1 for absorption, distribution, metabolism, and excretion/toxicology studies.

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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]