Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways

Abstract

Glutathione S-transferase (GST) zeta (GSTZ1-1) plays a significant role in the catabolism of phenylalanine and tyrosine, and a deficiency of GSTZ1-1 results in the accumulation of maleylacetoacetate and its derivatives maleylacetone (MA) and succinylacetone. Induction of GST subunits was detected in the liver of Gstz1 Ϫ/Ϫ mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins. The greatest induction was observed in members of the mu class. Induction of NAD(P)H:quinone oxidoreductase 1 and the catalytic and modifier subunits of glutamate-cysteine ligase was also observed.

Gene Frequencies of the Human GSTT1 (Null Allele) and GSTP1 (Ile105Val) Polymorphisms among South Indian Populations

“…Significant differences in GSTT1 null allele frequencies were observed between Caucasian, Asian, African and African American populations (Lee et al, 2008). The prevalence of GSTT1 null allele in the present study ranges from 11% to 22%, which is almost similar to the frequencies reported in Caucasians (Blackburn et al, 2006;Johansson et al, 1998;Mannervik et al, 2005). Korean population showed higher frequency of (45.3%) of GSTT1 null allele compared with the white Americans (20.4%), African Americans (21.8%), Mexican-Americans (9.7%) (Hoglund et al, 2009;Marinkovic et al, 2008) and Turkish populations (10.8-28.3%) (Oke et al, 1998;Shchipanov et al, 2008;Sura et al, 2008).…”

MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case–control study using a multilocus genotyping

“…Human GSTZ1, which is identical to maleylacetoacetate isomerase, catalyses two distinct reactions: the biotransformation of a range of α-haloacids, including dichloroacetic acid, a drinking water contaminant, and the GSH-dependent isomerization of maleylacetoacetate to fumarylacetoacetate, the penultimate step in the phenylalanine-tyrosine −/− mice display the induction of some of the cytosolic GST isoenzymes, and the constitutive expression of genes that are regulated by antioxidantresponse elements (AREs) and that respond to oxidative stress via the Keap1/Nrf2 signaling pathway, which regulates the expression of numerous detoxifying and antioxidant genes (Lim et al 2004;Lee and Johnson 2004). All of these findings support the view that the lack of GSTZ1 may induce oxidative stress (Blackburn et al 2006). The antioxidant role of GSTs is well known and derives essentially from their ability to regulate the concentration of GSH, the most powerful cellular antioxidant, in different cellular compartments including mitochondria, the principal source and target of ROS.…”

Susceptibility to Breast Cancer and Three Polymorphisms of GSTZ1

“…Induction of GST subunits was deleted in the liver of Gstz1 -/ -mice. The greatest induction was observed in members of mu class, especially Gstm1 (Lim et al, 2004;Blackburn et al, 2006). Based on published studies, at least some of the genetic polymorphisms are significantly associated with multifactorial traits only among specific ethnic groups (Hung et al, 2005;Kiyohara et al, 2006;Saadat, 2006;Saadat and Ansari-Lari, 2009).…”

“…In mice and human, the GSTz are expressed in many tissues at a low level (Blackburn et al, 2006). In mice, Gstz1 deficiency resulted in the generation of a constant level of oxidative stress (Blackburn et al, 2006). Several GSTZ1 variant sequences have been identified in humans (Blackburn et al, 2000;Fang et al, 2006).…”

“…The GSTz are expressed in a spectrum of species ranging from plants to humans and is a highly conserved class of GSTs during the course of evolution (Board et al, 1997;Sheehan et al, 2001). In mice and human, the GSTz are expressed in many tissues at a low level (Blackburn et al, 2006). In mice, Gstz1 deficiency resulted in the generation of a constant level of oxidative stress (Blackburn et al, 2006).…”