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

Abstract

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.

Mice Lacking Three Loci Encoding 14 Glutathione Transferase Genes: A Novel Tool for Assigning Function to the GSTP, GSTM, and GSTT Families

“…For example, comparison of the activity of extracts from GstmD/D mice and Gstm12/2 mice indicates that Gstm2 through Gstm7 do not contribute significantly to the metabolism of DCNB, even though the expression of Gstm2, Gstm3, Gstm6, and Gstm4 in the liver has been reported (Knight et al, 2007). Interestingly, metabolism of DCNB by human GSTM1 has not been supported in comparative studies using extracts from individuals carrying the null GSTM1 allele (Arakawa et al, 2012). Therefore, this substrate may be highly specific for a single murine Gstm1 gene, calling into question the evolutionary and functional relationship between the mouse and human Gstm isoforms (Board, 2007).…”

Resistance to acetaminophen-induced hepatotoxicity in <i>glutathione S-transferase Mu 1</i>-null mice

“…Gstm1-and Gstt1-null mice have been developed by our group (Fujimoto et al, 2006(Fujimoto et al, , 2007, since null genotypes of human GSTs have been reported to occur exclusively in GSTM1 and GSTT1 (Hayes et al, 2005). Gstm1-and Gstt1-null mice have the potential to be relevant models of humans with GSTM1-and GSTT1-null genotypes, since we showed the functional similarity between humans and mice for GSTM1 and GSTT1 toward some substrates (Arakawa et al, 2012). In addition, the resistance to APAP-induced hepatotoxicity in Gstp1/p2-null mice, which was described previously, prompted us to perform a study of APAP using Gst-null mice.…”

Species- and congener-differences in microcystin-LR and -RR GSH conjugation in human, rat, and mouse hepatic cytosol

“…Some individuals characterized, for example, by double null M1 and T1 mutation, endowed with a decreased level of GST activity, may experience a lower formation of conjugates and a longer half-life of the parent compound, resulting in a higher risk of MC-induced toxic effects, especially when combined to GSH depletion. The use of knockout mouse strains may potentially help in understanding the relevance of human null phenotype and its covering by the inter-individual variability default factor of 10, but it is known that, depending on the used substrate, the impact of GST-null genotypes in human and mice is not always the same (Arakawa et al, 2012). Therefore the use of phenotyped human cytosol samples could be useful.…”