Evaluation of Hepatic Glutathione S-Transferase Mu 1 and Theta 1 Activities in Humans and Mice Using Genotype

Evaluation of Hepatic Glutathione S-Transferase Mu 1 and Theta 1 Activities in Humans and Mice Using Genotype
http://dmd.aspetjournals.org/content/early/2011/12/14/dmd.111.042911.full.pdf+html  (full text)

Shingo Arakawa1,4, Kazunori Fujimoto1, Ayako Kato1, Seiko Endo1, Aiko Fukahori1, Akira Shinagawa1, Thomas Fischer2, Juergen Mueller2 and Wataru Takasaki

Abstract
We investigated the impact of glutathione S-transferases Mu 1 (GSTM1)- and Theta 1 (GSTT1)-null genotypes on hepatic GST activities in humans, and compared the results with those of Gstm1- and Gstt1-null mice. In liver with GSTM1/Gstm1-null genotype, GST activity toward p-nitrobenzyl chloride (NBC) was significantly decreased in both humans and mice. Additionally, in liver with GSTT1/Gstt1-null genotype, GST activity toward dichloromethane (DCM) was significantly decreased in both humans and mice. Therefore, null genotypes of GSTM1/Gstm1 and GSTT1/Gstt1 are considered to decrease hepatic GST activities toward NBC and DCM, respectively, in both humans and mice. This observation shows the functional similarity of GSTM1 and GSTT1 toward some substrates between humans and mice. In the case of NBC and DCM, Gst-null mice would be relevant models for humans with GST-null genotype. In addition, decreases in GST activities toward 1,2-dichloro-4-nitrobenzene, trans-4-phenyl-3-buten-2-one, and 1-chloro-2,4,-dinitrobenzene were observed in Gstm1-null mice, and a decrease in GST activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was observed in Gstt1-null mice. However, an impact of GST-null genotypes on GST activities toward these substrates was not observed in humans. In the case of these mouse-specific substrates, Gst-null mice may be relevant models for humans regardless of GST genotype, since GST activities, which is higher in wild-type mice than in humans, were eliminated in Gst-null mice. This study shows that comparison of hepatic GST activities between humans and mice using genotype information would be valuable in utilization of Gst-null mice as human models.