Methemoglobinemia induced by 1,2-dichloro-4-nitrobenzene in mice with a disrupted glutathione S-transferase Mu 1 gene.
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.
Arakawa
Shingo
S
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka, Japan. arakawa.shingo.z6@daiichisankyo.co.jp
Maejima
Takanori
T
Kiyosawa
Naoki
N
Yamaguchi
Takashi
T
Shibaya
Yukari
Y
Aida
Yoshie
Y
Kawai
Ryota
R
Fujimoto
Kazunori
K
Manabe
Sunao
S
Takasaki
Wataru
W
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009578:Nitrobenzenes / Q000633:toxicity*
D017931:DNA Primers; D009578:Nitrobenzenes; C028328:1,2-dichloro-4-nitrobenzene; D005982:Glutathione Transferase