HGNC Approved Gene Symbol: GSTT1
Cytogenetic location: 22q11.2 Genomic coordinates (GRCh38): 22:17,400,001-25,500,000
Glutathione S-transferases catalyze the conjugation of glutathione to a wide range of potential toxins as the first step in detoxification. The GSTs form a superfamily whose dimeric proteins have been placed into several multigene families. For background information on GSTs, see 138350.
For a long time the glutathione S-transferases of the theta class were largely overlooked because of their low activity with the model substrate 1-chloro-2,4-dinitrobenzene (CDNB) and their failure to bind to immobilized glutathione affinity matrices. Pemble et al. (1994) reported the cDNA cloning of a human theta-class GST, termed GSTT1. The deduced 239-amino acid GSTT1 protein shares 80% sequence identity with the rat homolog.
By in situ hybridization studies, Webb et al. (1996) mapped the GSTT1 gene to 22q11.2, the same band where GSTT2 (600437) is localized.
In humans, glutathione-dependent conjugation of halomethane is polymorphic, with 60% of the population classed as conjugators and 40% as nonconjugators. From PCR and Southern blot analyses, Pemble et al. (1994) showed that the GSTT1 gene was absent from 38% of the population. The presence or absence of the gene was coincident with the conjugator (GSTT1+) and nonconjugator (GSTT1-) phenotypes, respectively. The GSTT1+ phenotype can catalyze the glutathione conjugation of dichloromethane, a metabolic pathway that had been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and was believed to be responsible for the carcinogenicity of dichloromethane in the mouse. In humans, the GSTT1 enzyme is found in the erythrocyte and this may act as a detoxification sink. Thus, Pemble et al. (1994) stated that characterization of the GSTT1 polymorphism would enable a more accurate assessment of human health risk from synthetic halomethanes and other industrial chemicals.
Chen et al. (1996) compared the frequency of the GSTT1 null genotype in 96 patients with myelodysplastic syndromes (MDS) and 201 cancer-free controls of similar age, race, and sex. The frequency of the GSTT1 null genotype was 46% among MDS cases and 16% among controls. Inheritance of the GSTT1 null genotype was calculated to confer a 4.3-fold increased risk of MDS. The GSTM1 null genotype (138350) was not associated with an increased risk of MDS. The authors suggested that the mechanism of the association might be decreased detoxification of environmental or endogenous carcinogens.
Patients with reduced ability to metabolize environmental carcinogens or toxins may be at risk of developing aplastic anemia. GST has been implicated in detoxifying mutagenic electrophilic compounds. Lee et al. (2001) investigated whether homozygous deletions of GSTM1 and GSTT1 affect the likelihood of developing aplastic anemia. They found that the incidence of GSTM1 and GSTT1 gene deletions was significantly higher for aplastic anemia patients than for healthy controls (odds ratio = 3.1, P = 0.01, and odds ratio = 3.1, P = 0.004, respectively). Among the aplastic anemia patients, 17.5% had chromosomal abnormalities at the time of diagnosis, and all aplastic anemia patients with chromosomal abnormalities showed GSTT1 gene deletions.
Chen et al. (1996) described a method for simultaneous characterization of GSTM1 and GSTT1 and studied the genotypes in whites and blacks. The frequency of the null genotype for GSTM1 (GSTM1-) was higher in whites and that for GSTT1- was higher in blacks. The observed frequency of the 'double null' genotype was not significantly different from that predicted, assuming that the 2 polymorphisms are independent and did not differ by race or sex.
Individual differences in the metabolism of methyl bromide, ethylene oxide, and methylene chloride in human blood have been attributed to the genetic polymorphism of GSTT1 (Peter et al., 1989; Pemble et al., 1994). Depending on the GSTT1 enzyme activity toward methyl chloride measured in erythrocytes, an individual can be assigned to 1 of 3 groups: nonconjugators, low conjugators, and high conjugators (Hallier et al., 1990). Several studies have shown a difference in susceptibility toward toxic effects in nonconjugators and conjugators. Genotoxic effects such as induction of sister chromatid exchanges (SCE) after exposure of human blood to methyl bromide and other agents in vitro were found to be more pronounced in nonconjugators. Even the background levels of SCE were higher in the nonconjugator phenotype (Schroder et al., 1995). It is generally assumed that the nonconjugator phenotype is a result of the homozygous presence of a nonfunctional GSTT1 allele (GSTT1*0). This allele represents a partial or complete deletion at the GSTT1 gene locus.
Wiebel et al. (1999) studied 29 persons in 3 generations of a large family; phenotyping and genotyping with respect to GSTT1 was performed. The GSTT1 enzyme activity of high conjugators was twice as high as that of low conjugators. The distribution of GSTT1 phenotypes strongly indicated a mendelian intermediary inheritance, in which a gene-dosage effect results in a doubled enzyme expression in the presence of 2 functional alleles. The mendelian intermediary inheritance was further supported by the finding of a semiquantitative PCR method designed to distinguish the 3 genotypes of GSTT1 for rapid screening of large study groups.
Numerous studies have shown that maternal cigarette smoking during pregnancy is associated with reduced birth weight and increased risk of low birth weight, defined as weight less than 2,500 g. Maternal cigarette smoking has thus been identified as the single largest modifiable risk factor for intrauterine growth restriction in developed countries. However, not all women who smoke cigarettes during pregnancy have low-birth weight infants. Wang et al. (2002) studied whether the association between maternal cigarette smoking and infant birth weight differs by polymorphisms of 2 maternal metabolic genes: CYP1A1 and GSTT1 (600436). The CYP1A1 polymorphism was the Msp1 polymorphism (AA vs Aa and aa); the GSTT1 polymorphism was present versus absent. Wang et al. (2002) found that regardless of genotype, continuous maternal smoking during pregnancy was associated with a mean reduction of 377 g in birth weight. They found that for the CYP1A1 genotype, the estimated reduction in birth weight was 252 g for the AA genotype group, but was 520 g for the Aa/aa genotype group. For the GSTT1 genotype, they found the estimated reduction in birth weight was 285 g and 642 g for the present and absent genotype groups, respectively. When both CYP1A1 and GSTT1 genotypes were considered, Wang et al. (2002) found the greatest reduction in birth weight among smoking mothers with the CYP1A1 Aa/aa and GSTT1 absent genotypes. Among mothers who had not smoked during their pregnancy or during the 3 months prior to their pregnancy, genotype did not independently confer an adverse effect.
Chen, C.-L., Liu, Q., Relling, M. V. Simultaneous characterization of glutathione S-transferase M1 and T1 polymorphisms by polymerase chain reaction in American whites and blacks. Pharmacogenetics 6: 187-191, 1996. [PubMed: 9156696] [Full Text: https://doi.org/10.1097/00008571-199604000-00005]
Chen, H., Sandler, D. P., Taylor, J. A., Shore, D. L., Liu, E., Bloomfield, C. D., Bell, D. A. Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet 347: 295-297, 1996. [PubMed: 8569364] [Full Text: https://doi.org/10.1016/s0140-6736(96)90468-7]
Hallier, E., Jaeger, R., Deutschmann, S., Bolt, H. M., Peter, H. Glutathione conjugation and cytochrome P-450 metabolism of methyl chloride in vitro. Toxicol. In Vitro 4: 513-517, 1990. [PubMed: 20702223] [Full Text: https://doi.org/10.1016/0887-2333(90)90109-7]
Lee, K. A., Kim, S. H., Woo, H. Y., Hong, Y. J., Cho, H. C. Increased frequencies of glutathione S-transferase (GSTM1 and GSTT1) gene deletions in Korean patients with acquired aplastic anemia. Blood 98: 3483-3485, 2001. [PubMed: 11719393] [Full Text: https://doi.org/10.1182/blood.v98.12.3483]
Pemble, S., Schroeder, K. R., Spencer, S. R., Meyer, D. J., Hallier, E., Bolt, H. M., Ketterer, B., Taylor, J. B. Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem. J. 300: 271-276, 1994. [PubMed: 8198545] [Full Text: https://doi.org/10.1042/bj3000271]
Peter, H., Deutschmann, S., Reichel, C., Hallier, E. Metabolism of methyl chloride by human erythrocytes. Arch. Toxicol. 63: 351-355, 1989. [PubMed: 2818198] [Full Text: https://doi.org/10.1007/BF00303122]
Schroder, K. R., Wiebel, F. A., Reich, S., Dannappel, D., Bolt, H. M., Hallier, E. Glutathione S-transferase (GST) theta polymorphism influences background SCE rate. Arch. Toxicol. 69: 505-507, 1995. [PubMed: 8526747] [Full Text: https://doi.org/10.1007/s002040050205]
Wang, X., Zuckerman, B., Pearson, C., Kaufman, G., Chen, C., Wang, G., Niu, T., Wise, P. H., Bauchner, H., Xu, X. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA 287: 195-202, 2002. [PubMed: 11779261] [Full Text: https://doi.org/10.1001/jama.287.2.195]
Webb, G., Vaska, V., Coggan, M., Board, P. Chromosomal localization of the gene for the human theta class glutathione transferase (GSTT1). Genomics 33: 121-123, 1996. [PubMed: 8617495] [Full Text: https://doi.org/10.1006/geno.1996.0167]
Wiebel, F. A., Dommermuth, A., Thier, R. The hereditary transmission of the glutathione transferase hGSTT1-1 conjugator phenotype in a large family. Pharmacogenetics 9: 251-256, 1999. [PubMed: 10376772]