TY - JOUR T1 - Characterization of Phenotypes in <em>Gstm1</em>-null Mice by Cytosolic and in Vivo Metabolic Studies Using 1,2-Dichloro-4-Nitrobenzene JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1495 LP - 1501 DO - 10.1124/dmd.106.010009 VL - 34 IS - 9 AU - Kazunori Fujimoto AU - Shingo Arakawa AU - Yukari Shibaya AU - Hiroaki Miida AU - Yosuke Ando AU - Hiroaki Yasumo AU - Ayako Hara AU - Minoru Uchiyama AU - Haruo Iwabuchi AU - Wataru Takasaki AU - Sunao Manabe AU - Takashi Yamoto Y1 - 2006/09/01 UR - http://dmd.aspetjournals.org/content/34/9/1495.abstract N2 - 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 AUC0–24 (5.1–5.3 times, versus the wild-type control) and higher Cmax (2.1–2.2 times, versus the wild-type control), with a correspondingly lower level of glutathione-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 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. The American Society for Pharmacology and Experimental Therapeutics ER -