title: Evaluation of hepatic glutathione transferase Mu 1 and Theta 1 activities in humans and mice using genotype information.
abstract: We investigated the impact of glutathione transferases Mu 1 (GSTM1)- and glutathione transferase 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. In addition, 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 between humans and mice for GSTM1 and GSTT1 toward some substrates. 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, because GST activities, which are 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 using Gst-null mice as human models.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan. arakawa.shingo.z6@daiichisankyo.co.jp
authors.forename: Shingo
authors.initials: S
authors.lastname: Arakawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Ayako
authors.initials: A
authors.lastname: Kato
authors.forename: Seiko
authors.initials: S
authors.lastname: Endo
authors.forename: Aiko
authors.initials: A
authors.lastname: Fukahori
authors.forename: Akira
authors.initials: A
authors.lastname: Shinagawa
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.forename: Juergen
authors.initials: J
authors.lastname: Mueller
authors.forename: Wataru
authors.initials: W
authors.lastname: Takasaki
mesh_terms: D000818:Animals; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008752:Methylene Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009578:Nitrobenzenes / Q000494:pharmacology; D011110:Polymorphism, Genetic; D013379:Substrate Specificity
chemical_list: D005982:Glutathione Transferase; D008752:Methylene Chloride; D009578:Nitrobenzenes; C027562:4-nitrobenzyl chloride; C413545:glutathione S-transferase T1