Methemoglobinemia induced by 1,2-dichloro-4-nitrobenzene in mice with a disrupted glutathione S-transferase Mu 1 gene.

Abstract

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.

• Authors: Shingo Arakawa, Takanori Maejima, Naoki Kiyosawa, Takashi Yamaguchi, Yukari Shibaya, Yoshie Aida, Ryota Kawai, Kazunori Fujimoto, Sunao Manabe, Wataru Takasaki
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 38 Issue 9 Pg. 1545-52 (Sep 2010) ISSN: 1521-009X [Electronic] United States
• PMID: 20562208 (Publication Type: Journal Article)

Chemical References

• DNA Primers
• Nitrobenzenes
• 1,2-dichloro-4-nitrobenzene
• Glutathione Transferase

Topics

• Animals
• Base Sequence
• DNA Primers
• Dose-Response Relationship, Drug
• Female
• Glutathione Transferase (genetics)
• Male
• Methemoglobinemia (chemically induced)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitrobenzenes (toxicity)