Disease relevance of GSTA1

• These results, although based on a small study population, describe an apparent difference in survival after treatment for breast cancer according to GSTA1 genotype [1].
• CONCLUSIONS: These findings suggest that the GSTA1 and GSTT1 polymorphisms are associated with prostate cancer susceptibility, especially among smokers [2].
• GSTP1 and GSTA1 polymorphisms interact with cruciferous vegetable intake in colorectal adenoma risk [3].
• A stereological grid point counting method was used to estimate the percent of cells staining positive for GSTA1 in normal prostate, PIA, HGPIN, and adenocarcinoma [4].
• The risk of colorectal cancer is associated not only with CYP2E1 high-activity alleles, but also GSTA1 low-activity alleles, among consumers of red or processed meat [5].

High impact information on GSTA1

• The data suggest that the most active glutathione-S-transferases in liver are the products of two autosomal loci, GST1 and GST2 [6].
• In conclusion, the measurement of GSTA provides a test of liver dysfunction that distinguishes women with ICP from those with PG [7].
• Serum concentrations of GSTA increased with gestation in ICP, being significantly higher from 24 (+/-2) weeks compared with controls (400% difference; 95% CI, 240%-734%; P < .001) [7].
• GSTA1/A2 and GSTP1 were found to be the most abundant GSTs in human lung, being present in the bronchial and bronchiolar epithelium of all individuals studied [8].
• This complex binds with extraordinary affinity to the active site of all these dimeric enzymes; GSTA1-1 shows the strongest interaction (KD congruent with 10-10 m), whereas GSTM2-2 and GSTP1-1 display similar and slightly lower affinities (KD congruent with 10-9 m) [9].

Chemical compound and disease context of GSTA1

• Human hematopoietic CD34+ cells and bone marrow do not express GSTA1 message, which was present at a high level in liver, an organ relatively resistant to busulfan toxicity in comparison to bone marrow [10].
• Glutathione S-transferase (GSTM1, GSTT1 and GSTA1) polymorphisms and outcomes after treatment for acute myeloid leukemia: pharmacogenetics in Southwest Oncology Group (SWOG) clinical trials [11].
• We have expressed human glutathione S-transferases GSTA1-1 and GSTP1-1 in Salmonella typhimurium TA100 in order to assess the ability of these enzymes to modulate the mutagenicity of 1,2-dibromo-3-chloropropane (DBCP) and tris(2,3-dibromopropyl)phosphate (Tris-BP) [12].
• Our findings in a relevant human model system are supportive of a protective role of GSH and hGSTA1 against phenytoin toxicity and teratogenesis [13].
• Glutathione S-transferases as antioxidant enzymes: small cell lung cancer (H69) cells transfected with hGSTA1 resist doxorubicin-induced apoptosis [14].

Biological context of GSTA1

• Polymerase chain reaction/restriction fragment length polymorphism analysis revealed the existence of three variants, a silent base substitution, K125K (G365A) in GSTA1, and T112S and E210A in GSTA2, in European Australian, African and Chinese populations [15].
• A genetic polymorphism in the 5'-regulatory sequence of hGSTA1 has been shown to correlate with the relative and absolute levels of expression of GSTA1/GSTA2 in human liver [16].
• Transfection with hGSTA1 or hGSTA2 protected these cells from H2O2- and naphthalene-induced LPO and attenuated H2O2- and naphthalene-induced apoptosis through inhibiting caspase 3 activation [17].
• Protection of HLE B-3 cells against hydrogen peroxide- and naphthalene-induced lipid peroxidation and apoptosis by transfection with hGSTA1 and hGSTA2 [17].
• This suggests that NF-kappaB and PI3-kinase signaling pathways play a role in GSTA1 gene expression [18].

Anatomical context of GSTA1

• The 3 cell lines which expressed GSTA1 were all erythroid [19].
• This implies a greater cytoprotective role for GSTT1 and GSTA1 in erythroid cells and GSTM1 in lymphoid cells [19].
• These consistent patterns of expression would suggest that compared to duodenum and small intestine, colon and to a lesser extent stomach always have low potential for GST-dependent detoxification of chemical carcinogens and are therefore at greater risk of genotoxic effects, particularly via substrates that are specific for GSTA1 [20].
• Similarly, mean levels of hGSTA1 protein expression in liver cytosols decreased significantly according to genotype: hGSTA1*A > hGSTA1-heterozygous > hGSTA1*B [21].
• HLE B-3 cell membranes were prepared, peroxidized, and used to examine whether hGSTA1-1 and hGSTA2-2 catalyzes the reduction of membrane PL-OOH in situ using the microiodometric and spectrophotometric assays [17].

Associations of GSTA1 with chemical compounds

• Screening of the Alpha class glutathione transferases (GSTs) in the EST database identified 10 putative polymorphisms in the coding region of the GSTA1 and GSTA2 genes, six of which were subsequently verified by sequence analysis [15].
• A recently described polymorphism alters hepatic expression of GSTA1, a GST with high activity in glutathione conjugation of metabolites of cyclophosphamide (CP) [1].
• The prostate has potential for GSTP1-dependent detoxification of ATP-activated N-hydroxy-PhIP but little potential for detoxification of N-acetoxy-PhIP by GSTA1 [22].
• Vmax/KM for GSTA1-1 was 7.95 microliters/min/mg protein, the highest busulfan-conjugating activity of all human liver and placenta isoforms evaluated [23].
• Many of the cells within PIA lesions contain elevated levels of GSTP1, glutathione S-transferase-alpha (GSTA1), and cyclooxygenase-II proteins, suggesting a stress response [24].

Regulatory relationships of GSTA1

• The encoded GSTA4-4 enzyme was expressed in Escherichia coli and was found to be immunologically distinct from GSTA1-1 and to have high activity with alk-2-enals [25].
• However, the MEK inhibitor PD98059 enhanced significantly the induction of GSTA1 by sulforaphane [18].

Other interactions of GSTA1

• Conversely, mean hGSTA2 expression increased according to the same order of hGSTA1 genotype [21].
• As expected, the GSTM1 and GSTT1 deletion polymorphisms, and the GSTA1 g.-69C-->T polymorphism significantly affected the respective isoenzyme levels [26].
• GSTA1 genotype was determined by polymerase chain reaction and restriction fragment length polymorphism [1].
• Sulforaphane and its glutathione conjugate but not sulforaphane nitrile induce UDP-glucuronosyl transferase (UGT1A1) and glutathione transferase (GSTA1) in cultured cells [27].
• Western blotting of prenatal liver proteins provided corroborating evidence via detection of an hGSTA1/2-reactive protein in both cytosol and mitochondria and of hGSTA4-4-reactive protein in mitochondria alone [28].

Analytical, diagnostic and therapeutic context of GSTA1

• RT-PCR results verified a reduction in the expression of GSTA1 [29].
• In this study we determined the frequencies of allelic variants of GSTA1 and GSTT1 in a Japanese population using PCR-restriction fragment length polymorphism and allele-specific PCR [30].
• CONCLUSIONS: We have failed to demonstrate within the limitation of a case-control study a reproducible significant association of GST polymorphisms with susceptibility to ALD but there are suggestions that GSTA1 and GSTT1 warrant further study [31].
• METHODS: We performed immunohistochemistry against GSTA1 on formalin-fixed radical prostatectomies (n = 45) [4].
• The frequency of GSTA1 *A/*B or *B/*B genotype was 24.3% in urothelial cancer cases, compared with 21.2% in the control groups (OR=1.22; 95%CI 0.87-1.72) after adjustment for age, gender and smoking status [32].

References