TY - JOUR T1 - Methemoglobinemia Induced by 1,2-Dichloro-4-nitrobenzene in Mice with a Disrupted <em>Glutathione S-Transferase Mu 1</em> Gene JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1545 LP - 1552 DO - 10.1124/dmd.110.033597 VL - 38 IS - 9 AU - Shingo Arakawa AU - Takanori Maejima AU - Naoki Kiyosawa AU - Takashi Yamaguchi AU - Yukari Shibaya AU - Yoshie Aida AU - Ryota Kawai AU - Kazunori Fujimoto AU - Sunao Manabe AU - Wataru Takasaki Y1 - 2010/09/01 UR - http://dmd.aspetjournals.org/content/38/9/1545.abstract N2 - 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. ER -