Disease relevance of Gsta4

• The contribution of CYP2E1 and GSTA4-4 in neuronal toxicity has also been reported [1].
• The administration of 20 mg tannic acid/kg body weight three times a week every other day for three weeks, enhanced the endogenous antioxidant capacity of the cells by increasing the activities of antioxidant enzymes (SOD, CAT, GSH-R, GST), GSH content and serum Cu and Zn levels [2].
• Mice homozygous for the disrupted mGsta4 allele were viable and appeared normal except for lower litter size, higher fat content in bones, and greater susceptibility to bacterial infection [3].
• GST-mu was not detected in either L1210 leukemia lines [4].
• Continuous infusion of 10 micrograms/kg/h of octreotide yielded plasma levels of 5.7 ng/ml and elicited highly significant growth inhibitory effects on solid ZR-75-1 breast tumors in nude mice [5].

Psychiatry related information on Gsta4

• Intraperitoneal injection of pHYB-TBLV transfectants consistently resulted in T-cell lymphomas in 50% of injected weanling BALB/c mice with an average latency period of 5.7 (+/- 1.5) months [6].
• The results of these studies suggest that GST 8-8, and possibly other related GST isozymes, may play an important role in defense mechanisms against lipid peroxidation [7].

High impact information on Gsta4

• In this study, we show that the proteolytic cleavage of a GST-huntingtin fusion protein leads to the formation of insoluble high molecular weight protein aggregates only when the polyglutamine expansion is in the pathogenic range [8].
• A fragment of 5.7 kilobases of this clone was completely sequenced and found to contain a pseudogene whose sequence is highly homologous to the sequences of known transplantation antigens [9].
• This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG [10].
• Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB) [10].
• Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress [10].

Chemical compound and disease context of Gsta4

• The ability of the two Alpha class subunit interfaces to adopt a functional heterodimeric structure has been investigated here.The heterodimer GST A1-4 was obtained by co-expression of the two human Alpha class subunits A1 and A4 in Escherichia coli [11].
• Cutaneous xenobiotic metabolizing enzymes including aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECD), epoxide hydrolase (EH) and glutathione S-transferase (GST) activities were examined in SKH hairless mice chronically irradiated with UVB to induce squamous cell carcinoma (SCC) [12].
• In the present study, the effect of tumor necrosis factor (TNF)-alpha and lipopolysaccharides (LPS) on the constitutive and inducible expression of the AHR-regulated genes cyp1a1, GST Ya, and QOR was determined in murine hepatoma Hepa 1c1c7 (WT), AHR-deficient (C12), and AHR nuclear translocator protein (ARNT)-deficient (C4) cells [13].
• Phase 1 clinical evaluation of oltipraz has demonstrated its ability to induce GST activity as well as the level of transcripts encoding gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase in the colon mucosa of individuals at increased risk for colorectal cancer [14].
• Expression vector pGEX2T was transfected into E. coli (BL-21) and hEGF-CH1 expressed by induction of the lac Iq promotor with 50 microM isopropyl beta-D-thiogalactopyranoside (IPTG). hEGF- CH1 fused to glutathione S-transferase (GST) was isolated and purified by affinity chromatography [15].

Biological context of Gsta4

• Analysis of the xenobiotic metabolizing genes in the two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1 [16].
• mGSTA4-4, a murine glutathione S-transferase (GST) exhibiting high activity in conjugating the lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) with glutathione (GSH), was crystallized in complex with the GSH conjugate of 4-HNE (GS-Hna) [17].
• It resembles the structure of other members of the GST superfamily, but reveals a distinct substrate binding site [18].
• A full-length cDNA clone encoding the previously purified mouse glutathione S-transferase GST 5.7 [(1991), Biochem. J. 278, 793-799] has been isolated from a mouse lung cDNA library in lambda gt11 [19].
• 6. These results provided evidence that ATB stimulated mEH and GST gene expression at early times and reduced the P4502C11 level in the absence of P4502E1 suppression [20].

Anatomical context of Gsta4

• Protein kinase activators (cAMP, forskolin, or phorbol-12-myristate-13-acetate) markedly increased GSTA4-4 targeting to mitochondria, whereas kinase inhibitors caused its retention in the cytosol [21].
• Immunoinhibition and immunodepletion studies showed that the Hsp70 chaperone is required for the efficient translation of GSTA4-4 as well as its translocation to mitochondria [21].
• In this study, we have investigated the mechanism of mouse GSTA4-4 targeting to mitochondria, using a combination of in vitro mitochondrial import assay and in vivo targeting in COS cells transfected with cDNA [21].
• In the present study, we have investigated the nature of the glutathione S-transferase (GST) pool in mouse liver mitochondria, and have purified three distinct forms of GST: GSTA1-1 and GSTA4-4 of the Alpha family, and GSTM1-1 belonging to the Mu family [22].
• After a 12-amino acid residue membrane-translocating sequence (MTS) was fused to the C-terminus of glutathione S-transferase (GST), the resultant GST-MTS fusion proteins were efficiently imported into NIH 3T3 fibroblasts and other cells [23].

Associations of Gsta4 with chemical compounds

• Comparison of peptide maps of GST 5.7 with those representative of Alpha, Mu and Pi class GST isoenzymes of mouse lung showed that it had a distinct peptide fragmentation pattern [24].
• In the enzymatic study, GST activities toward 1,2-dichloro-4-nitrobenzene (DCNB) and 1-chloro-2,4-dinitrobenzene (CDNB) in the liver and kidney cytosols were markedly lower in Gstm1-null mice than in the wild-type control [25].
• Drastic decrease in endogenous enzymes (GSH, GST, catalase and SOD) and total thiols was observed in irradiated mice at 2, 4 and 8 h post irradiation, while pretreatment with morin (100 mg/kg) prevented this decrease [26].
• The resulting mGsta4 null mouse expressed no mGsta4 mRNA and no corresponding protein, had a reduced ability to conjugate 4-HNE, and had an increased steady-state level of this aldehyde in tissues [3].
• LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout [27].

Enzymatic interactions of Gsta4

• However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH) [28].

Other interactions of Gsta4

• Gstm1-null mice had GST activities of only 6.1 to 21.0% of the wild-type control to DCNB and 26.0 to 78.6% of the wild-type control to CDNB [25].
• The IL-6 activity in supernatants induced by 500 micrograms/ml Poly I-C (58.4 +/- 16.4 U/ml; n = 4) was higher than that evoked by 100 U/ml beta IL-1 (5.7 +/- 0.4 U/ml) or 500 micrograms/ml Poly A-U (39.6 +/- 7.8 U/ml) [29].
• Treatment of rat with ATB (20-50 mg/kg/day for 5 days) resulted in 2-3-fold increases in mEH, rGSTA1/2, rGSTA3/5 and rGSTM1 mRNA levels with the induction of GST subunits [20].
• Aqueous black tea extract was given as a pretreatment to group IV mice at a dose of 200 mg ml(-1) polyphenols before the pesticide dose, which significantly decreased the levels of lipid peroxidation and significantly elevated the activities of SOD, CAT, GSH, total thiol, GPx, GR and GST in liver to levels similar to the controls [30].
• Morin (100 mg/kg) also significantly elevated the endogenous antioxidant enzymes viz. glutathione S transferase (GST), superoxide dismutase (SOD) and reduced glutathione (GSH), in normal mice at 2, 4 and 8 h post treatment [26].

Analytical, diagnostic and therapeutic context of Gsta4

• Immunoblotting class-alpha and class-mu GST showed that constitutive expression of most transferase subunits is also reduced in the small intestine of Nrf2 mutant mice [31].
• Immunohistochemistry revealed that induction of NQO1, class-alpha GST, and GCS(h) occurs primarily in epithelial cells of the small intestine [31].
• Both homodimers of mGTmu1 and mGTmu2 and an apparent heterodimer are formed in L929 cells, as demonstrated by the isoelectric focusing profile of GST purified from this cell line [32].
• Irradiation of mouse liver cytosol in the presence of [3H]methyltrienolone, followed by immunoprecipitation using GST-specific antibodies established that both GST mu and GST alpha bind [3H]methyltrienolone and both contribute to the affinity-labelled protein designated MBP27 [33].
• Alterations in GST isozyme expression were confirmed by Western and Northern blot [34].

References