Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: GSTP1
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38): 11:67,583,812-67,586,653 (from NCBI)
Glutathione S-transferases (GSTs; EC 2.5.1.18) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. Based on their biochemical, immunologic, and structural properties, the mammalian cytosolic GSTs are divided into several classes, including alpha (e.g., 138359), mu (e.g., 138350), kappa (602321), theta (e.g., 600436), pi, omega (e.g., 605482), and zeta (e.g., 603758). In addition, there is a class of microsomal GSTs (e.g., 138330). Each class is encoded by a single gene or a gene family.
By screening a human placenta cDNA library with a rat placenta GST (GSTP) cDNA, Kano et al. (1987) isolated GST-pi cDNAs. The predicted 209-amino acid protein shares 86% sequence identity with GSTP. However, GST-pi has a pI of 5.5, while that of GSTP is 6.9. Northern hybridization revealed that GST-pi is expressed as a 750-nucleotide mRNA in liver. Moscow et al. (1988) cloned cDNA corresponding to the anionic isozyme of glutathione S-transferase (GST-pi), one of the drug-detoxifying enzymes overexpressed in multidrug-resistant cells. Board et al. (1989) isolated a partial cDNA clone of GST3 from a human lung cDNA library using antiserum to human lung GST3. The sequence showed 2 base differences from that of GST3 isolated from a human placenta cDNA library.
Kingsley et al. (1989) and Seldin et al. (1991) concluded that Gsta of the mouse is homologous to human GST2 (138360), not GST3.
Morrow et al. (1989) reported that the GST-pi gene contains 7 exons and spans approximately 2.8 kb.
Using an X;11 translocation segregating in hybrids, Silberstein et al. (1982) and Silberstein and Shows (1982) showed that the GST3 gene, which they called GST1, is located in the p13-qter region of chromosome 11. Laisney et al. (1983) concluded that the GST gene localized to chromosome 11 by Silberstein and Shows (1982) was GST3. They assigned the gene to 11q13-q22. Suzuki and Board (1984) also stated that the glutathione S-transferase gene that was mapped to chromosome 11 was GST3, not GST1.
Moscow et al. (1988) and Board et al. (1989) mapped the GST-pi gene to 11q13 using in situ hybridization. Using a panel of human-rodent somatic cell hybrids and a DNA probe specific for the class, Islam et al. (1989) mapped GST3, called by them a class pi gene, to chromosome 11. By study of somatic cell hybrids, Konohana et al. (1990) confirmed the assignment of the GST3 gene to 11q. Smith et al. (1995) refined the localization of the GSTP1 gene by study of radiation-reduced somatic cell hybrids. They identified a tandem repeat polymorphism in the 5-prime region and used it for linkage analysis to demonstrate that GSTP1 is 5 cM distal to PYGM (608455) and 4 cM proximal to FGF3 (164950).
Rochelle et al. (1992) indicated that the mouse Gst3 locus is on proximal chromosome 19.
Pseudogenes
In in situ hybridization studies that assigned the GSTP1 gene to 11q13, Board et al. (1989) found an additional hybridizing locus at 12q13-q14. Board et al. (1992) demonstrated that this closely related Pi class glutathione S-transferase gene is, in fact, a partial reverse-transcribed pseudogene.
Laisney et al. (1984) stated that GST3 is present in all tissues and cells, with the exception of red cells, in which only erythrocyte GST (GSTe) is observed. Furthermore, GSTe, the electrophoretically fastest and most thermolabile of different GSTs analyzed, is found only in erythrocytes. In leukocytes, only GST3 is found. Beutler et al. (1988), quoting Board (1981), stated that the enzyme in red cells is designated GST3 (or GST-rho) and is different from the major liver enzymes GST1 and GST2 (GSTA2; 138360). The function of the red cell enzyme is not known, but the red cell membrane contains transport systems that actively transport glutathione-xenobiotic conjugates from the red cell. Thus, GST may serve to rid the red cell, and perhaps to scavenge the bloodstream, of foreign molecules.
Moscow et al. (1989) compared the expression of GST-pi in several normal and malignant tissues. They found that GST-pi expression was increased in many tumors relative to matched normal tissue. Konohana et al. (1990) demonstrated that GST3 is abundantly expressed in human skin.
Bora et al. (1991) identified GST-pi as fatty acid ethyl ester synthase III (FAEES3), a heart enzyme that metabolizes ethanol nonoxidatively. Transfection of FAEES3 cDNA into MCF7 cells resulted in a 14-fold increase in synthase activity and a 12-fold increase in glutathione S-transferase activity. Transfection of MCF7 cells with placental GST cDNA resulted in a 13-fold increase in GST activity but no increase in synthase activity. Board et al. (1993) found that the protein described by Bora et al. (1991) had no FAEES or GST activity when expressed in E. coli and suggested that the cDNA may have resulted from a cloning artifact.
Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, this metabolite, NAPQI, is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases, including GSTP1. To assess the role of GST in acetaminophen hepatotoxicity, Henderson et al. (2000) examined acetaminophen metabolism and liver damage in mice null for Gstp, i.e., Gstp1/p2 -/-. Contrary to their expectations, instead of being more sensitive, the null mice were highly resistant to the hepatotoxic effects of this compound. The data demonstrated that GSTP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound.
Ali-Osman et al. (1997) isolated cDNAs corresponding to 3 polymorphic GSTP1 alleles, GSTP1*A (134660.0001), GSTP1*B (134660.0002), and GSTP1*C (134660.0003), expressed in normal cells and malignant gliomas. The variant cDNAs result from A-to-G and C-to-T transitions at nucleotides 313 and 341, respectively. The transitions changed codon 105 from ATC (ile) in GSTP1*A to GTC (val) in GSTP1*B and GSTP1*C, and changed codon 114 from GCG (ala) to GTG (val) in GSTP1*C. Both amino acid changes are in the electrophile-binding active site of the GST-pi peptide. Computer modeling of the deduced crystal structures of the encoded peptides showed significant deviations in the interatomic distances of critical electrophile-binding active site amino acids as a consequence of the amino acid changes. The encoded proteins expressed in E. coli and purified by GSH affinity chromatography showed a 3-fold lower K(m) and a 3- to 4-fold higher K(cat)/K(m) for the GSTP1*A-encoded protein than the proteins encoded by GSTP1*B and GSTP1*C. Analysis of 75 cases showed the relative frequency of GSTP1*C to be 4-fold higher in malignant gliomas than in normal tissues. These data provided conclusive molecular evidence of allelopolymorphism of the human GSTP1 locus, resulting in active, functionally different GSTP1 proteins, and laid the groundwork for studies of the role of this gene in xenobiotic metabolism, cancer, and other human diseases.
Allan et al. (2001) hypothesized that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help identify individuals at increased risk of developing t-AML. To this end, Allan et al. (2001) examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in these 3 GSTs. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. At least 1 GSTP1 valine-105 allele (see 134660.0002 and 134660.0003) was found more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34), than in patients with de novo AML, and not among those t-AML patients with prior exposure to radiotherapy alone (OR, 1.01). These data suggested that inheritance of at least 1 GSTP1 valine-105 allele confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.
Beutler et al. (1988) found unexplained red cell GST deficiency in an otherwise healthy adult male with mild hemolytic anemia accompanied by splenomegaly, indirect hyperbilirubinemia, and cholelithiasis. Residual enzyme activity was only about 15% of mean normal. Because he was adopted and childless, the hereditary nature of the defect could not be established. Modest decreases in leukocyte and platelet GST activities were documented.
Menegon et al. (1998) pursued the hypotheses that Parkinson disease (168600) is secondary to the presence of neurotoxins and that pesticides are possible causative agents. Because glutathione transferases metabolize xenobiotics, including pesticides, they investigated the role of GST polymorphisms in the pathogenesis of idiopathic Parkinson disease. In 95 Parkinson disease patients and 95 controls, they genotyped PCR polymorphisms in 4 GST classes: GST1, GSTT1 (600436), GSTP1, and GSTZ1 (603758). Associations were found only with the GSTP1 polymorphisms. Analyzing the genotypes of those subjects who reported exposure to pesticides (39 patients and 26 controls), they found that the distribution of genotypes of the GSTP1 polymorphisms differed significantly between patients and controls. These differences seemed to be secondary to an excess of heterozygotes and noncarriers of A alleles among patients. Menegon et al. (1998) interpreted these results as suggesting that GSTP1, which is expressed in the blood-brain barrier, may influence response to neurotoxins and explain the susceptibility of some people to the parkinsonism-inducing effects of pesticides. In a commentary entitled 'Parkinson's Disease: Nature Meets Nurture,' Golbe (1998) pointed out that virtually every case-control study investigating the risk of Parkinson disease has shown that pesticide or herbicide exposure, or rural or farm experiences, increases Parkinson disease risk, typically 3-fold or 4-fold. Furthermore, rotenone, a commonly used pesticide, shares with the active metabolite of MPTP (a known cause of parkinsonism in humans and laboratory animals) the same neurotoxic action, namely inhibition of complex I, part of the mitochondrial respiratory enzyme chain.
Wilk et al. (2006) presented evidence suggesting that exposure to herbicides may be an effect modifier of the relationship between GSTP1 polymorphisms and age of onset in Parkinson disease.
Zusterzeel et al. (1999) found that GSTP1 is the main GST isoform in normal placental and decidual tissue. In preeclamptic (189800) women, they found lower median placental and decidual GSTP1 levels compared to those in controls. Zusterzeel et al. (1999) suggested that reduced levels of GSTP1 in preeclampsia may indicate a decreased capacity of the detoxification system, resulting in a higher susceptibility to preeclampsia. Among 113 preeclampsia trios (mother, father, and baby), Zusterzeel et al. (2002) found an increased frequency of the GSTP1 val105 polymorphism (see 134660.0002) in mothers, fathers, and offspring of preeclamptic pregnancies compared to controls. There was no significant difference in the GSTP1 allele frequencies in preeclamptic mothers, fathers, and offspring. The authors emphasized the paternal contribution to the risk for preeclampsia.
Gilliland et al. (2004) found that GSTP1 and GSTM1 modify the adjuvant effect of diesel exhaust particles on allergic inflammation. They challenged ragweed-sensitive patients intranasally with allergen alone and with allergen plus diesel exhaust particles and found that individuals with GSTM1 null or GSTP1 ile105 wildtype genotypes showed significant increases in IgE and histamine after challenge with diesel exhaust particles and allergens; the increase was largest in patients with both the GSTP1 ile/ile and GSTM1 null genotypes.
See 606581 for discussion of a possible association between variation in GSTP1 gene and susceptibility to polysubstance abuse.
Ali-Osman et al. (1997) identified 3 polymorphic forms of the GSTP1 gene. One allele, GSTP1*A, has ATC (ile) as codon 105 and GCG (ala) as codon 114. (Ali-Osman et al. (1997) had designated the substitutions ILE104 and ALA113 based on then-current numbering.)
Ali-Osman et al. (1997) identified 3 polymorphic forms of the GSTP1 gene. One allele, GSTP1*B, has GTC (val) as codon 105 and GCG (ala) as codon 114. (Ali-Osman et al. (1997) had designated the substitutions VAL104 and ALA113 based on then-current numbering.)
Ali-Osman et al. (1997) identified 3 polymorphic forms of the GSTP1 gene. One allele, GSTP1*C, has GTC (val) as codon 105 and GTG (val) as codon 114. (Ali-Osman et al. (1997) had designated the substitutions VAL104 and VAL113 based on then-current numbering.)
Ali-Osman, F., Akande, O., Antoun, G., Mao, J.-X., Buolamwini, J. Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants: evidence for differential catalytic activity of the encoded proteins. J. Biol. Chem. 272: 10004-10012, 1997. [PubMed: 9092542] [Full Text: https://doi.org/10.1074/jbc.272.15.10004]
Allan, J. M., Wild, C. P., Rollinson, S., Willett, E. V., Moorman, A. V., Dovey, G. J., Roddam, P. L., Roman, E., Cartwright, R. A., Morgan, G. J. Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc. Nat. Acad. Sci. 98: 11592-11597, 2001. Note: Erratum: Proc. Nat. Acad. Sci. 98: 15394 only, 2001. [PubMed: 11553769] [Full Text: https://doi.org/10.1073/pnas.191211198]
Awasthi, Y. C., Dao, D. D., Partridge, C. A. Genetic origin of human glutathione S-transferases. (Abstract) Am. J. Hum. Genet. 33: 35, 1981.
Beutler, E., Dunning, D., Dabe, I. B., Forman, L. Erythrocyte glutathione S-transferase deficiency and hemolytic anemia. Blood 72: 73-77, 1988. [PubMed: 3390613]
Board, P., Smith, S., Green, J., Coggan, M., Suzuki, T. Evidence against a relationship between fatty acid ethyl ester synthase and the pi class glutatione S-transferase in humans. J. Biol. Chem. 268: 15655-15658, 1993. [PubMed: 8340390]
Board, P. G. Biochemical genetics of glutathione-S-transferase in man. Am. J. Hum. Genet. 33: 36-43, 1981. [PubMed: 7468592]
Board, P. G., Coggan, M., Woodcock, D. M. The human Pi class glutathione transferase sequence at 12q13-q14 is a reverse-transcribed pseudogene. Genomics 14: 470-473, 1992. [PubMed: 1427860] [Full Text: https://doi.org/10.1016/s0888-7543(05)80243-5]
Board, P. G., Webb, G. C., Coggan, M. Isolation of a cDNA clone and localization of the human glutathione S-transferase 3 genes to chromosome bands 11q13 and 12q13-14. Ann. Hum. Genet. 53: 205-213, 1989. [PubMed: 2596826] [Full Text: https://doi.org/10.1111/j.1469-1809.1989.tb01786.x]
Bora, P. S., Bora, N. S., Wu, X., Lange, L. G. Molecular cloning, sequencing, and expression of human myocardial fatty acid ethyl ester synthase-III cDNA. J. Biol. Chem. 266: 16774-16777, 1991. [PubMed: 1885604]
Gilliland, F. D., Li, Y.-F., Saxon, A., Diaz-Sanchez, D. Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study. Lancet 363: 119-125, 2004. [PubMed: 14726165] [Full Text: https://doi.org/10.1016/S0140-6736(03)15262-2]
Golbe, L. I. Parkinson's disease: nature meets nurture. Lancet 352: 1328-1329, 1998. [PubMed: 9802266] [Full Text: https://doi.org/10.1016/s0140-6736(05)60741-6]
Henderson, C. J., Wolf, C. R., Kitteringham, N., Powell, H., Otto, D., Park, B. K. Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. Proc. Nat. Acad. Sci. 97: 12741-12745, 2000. [PubMed: 11058152] [Full Text: https://doi.org/10.1073/pnas.220176997]
Islam, M. Q., Platz, A., Szpirer, J., Szpirer, C., Levan, G., Mannervik, B. Chromosomal localization of human glutathione transferase genes of classes alpha, mu and pi. Hum. Genet. 82: 338-342, 1989. [PubMed: 2737666] [Full Text: https://doi.org/10.1007/BF00273994]
Kano, T., Sakai, M., Muramatsu, M. Structure and expression of a human class pi glutathione S-transferase messenger RNA. Cancer Res. 47: 5626-5630, 1987. [PubMed: 3664469]
Kingsley, D. M., Jenkins, N. A., Copeland, N. G. A molecular genetic linkage map of mouse chromosome 9 with regional localizations for the Gsta, T3g, Ets-1 and Ldlr loci. Genetics 123: 165-172, 1989. [PubMed: 2572508] [Full Text: https://doi.org/10.1093/genetics/123.1.165]
Konohana, A., Konohana, I., Schroeder, W. T., O'Brien, W. R., Amagai, M., Greer, J., Shimizu, N., Gammon, W. R., Siciliano, M. J., Duvic, M. Placental glutathione-S-transferase-pi mRNA is abundantly expressed in human skin. J. Invest. Derm. 95: 119-126, 1990. [PubMed: 2380573] [Full Text: https://doi.org/10.1111/1523-1747.ep12477830]
Laisney, V., Van Cong, N., Gross, M.-S., Parisi, I., Foubert, C., Weil, D., Frezal, J. Localisation du groupe syntenique LDHA-GST3-ESA4 sur le chromosome 11 chez l'homme: analyses des hybrides homme-rongeur classiques et d'un type nouveau (non adherents a la paroi). Ann. Genet. 26: 69-74, 1983. [PubMed: 6604488]
Laisney, V., Van Cong, N., Gross, M. S., Frezal, J. Human genes for glutathione S-transferases. Hum. Genet. 68: 221-227, 1984. [PubMed: 6500576] [Full Text: https://doi.org/10.1007/BF00418392]
Menegon, A., Board, P. G., Blackburn, A. C., Mellick, G. D., Le Couteur, D. G. Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet 352: 1344-1346, 1998. [PubMed: 9802272] [Full Text: https://doi.org/10.1016/s0140-6736(98)03453-9]
Morrow, C. S., Cowan, K. H., Goldsmith, M. E. Structure of the human genomic glutathione S-transferase-pi gene. Gene 75: 3-11, 1989. [PubMed: 2542132] [Full Text: https://doi.org/10.1016/0378-1119(89)90377-6]
Moscow, J. A., Fairchild, C. R., Madden, M. J., Ransom, D. T., Wieand, H. S., O'Brien, E. E., Poplack, D. G., Cossman, J., Myers, C. E., Cowan, K. H. Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res. 49: 1422-1428, 1989. [PubMed: 2466554]
Moscow, J. A., Townsend, A. J., Goldsmith, M. E., Whang-Peng, J., Vickers, P. J., Poisson, R., Legault-Poisson, S., Myers, C. E., Cowan, K. H. Isolation of the human anionic glutathione S-transferase cDNA and the relation of its gene expression to estrogen-receptor content in primary breast cancer. Proc. Nat. Acad. Sci. 85: 6518-6522, 1988. [PubMed: 2842775] [Full Text: https://doi.org/10.1073/pnas.85.17.6518]
Rochelle, J. M., Watson, M. L., Oakey, R. J., Seldin, M. F. A linkage map of mouse chromosome 19: definition of comparative mapping relationships with human chromosomes 10 and 11 including the MEN1 locus. Genomics 14: 26-31, 1992. [PubMed: 1358795] [Full Text: https://doi.org/10.1016/s0888-7543(05)80278-2]
Seldin, M. F., Saunders, A. M., Rochelle, J. M., Howard, T. A. A proximal mouse chromosome 9 linkage map that further defines linkage groups homologous with segments of human chromosomes 11, 15, and 19. Genomics 9: 678-685, 1991. [PubMed: 1674729] [Full Text: https://doi.org/10.1016/0888-7543(91)90361-h]
Silberstein, D. L., Sakaguchi, A. Y., Shows, T. B. Assignment of the gene for glutathione S-transferase-1 (GST1) to human chromosome 11. (Abstract) Cytogenet. Cell Genet. 32: 317, 1982.
Silberstein, D. L., Shows, T. B. Gene for glutathione S-transferase-1 (GST1) is on human chromosome 11. Somat. Cell Genet. 8: 667-675, 1982. [PubMed: 6958072] [Full Text: https://doi.org/10.1007/BF01542859]
Smith, C. M., Bora, P. S., Bora, N. S., Jones, C., Gerhard, D. S. Genetic and radiation-reduced somatic cell hybrid sublocalization of the human GSTP1 gene. Cytogenet. Cell Genet. 71: 235-239, 1995. [PubMed: 7587384] [Full Text: https://doi.org/10.1159/000134117]
Suzuki, T., Board, P. Glutathione-S-transferase gene mapped to chromosome 11 is GST3 not GST1. (Letter) Somat. Cell Molec. Genet. 10: 319-320, 1984. [PubMed: 6585974] [Full Text: https://doi.org/10.1007/BF01535254]
Wilk, J. B., Tobin, J. E., Suchowersky, O., Shill, H. A., Klein, C., Wooten, G. F., Lew, M. F., Mark, M. H., Guttman, M., Watts, R. L., Singer, C., Growdon, J. H., and 26 others. Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD study. Neurology 67: 2206-2210, 2006. [PubMed: 17190945] [Full Text: https://doi.org/10.1212/01.wnl.0000249149.22407.d1]
Zusterzeel, P. L. M., Peters, W. H. M., de Bruyn, M. A. H., Knapen, M. F. C. M., Merkus, H. M. W. M., Steegers, E. A. P. Glutathione S-transferase isoenzymes in decidua and placenta of preeclamptic pregnancies. Obstet. Gynec. 94: 1033-1038, 1999. [PubMed: 10576196] [Full Text: https://doi.org/10.1016/s0029-7844(99)00433-0]
Zusterzeel, P. L. M., te Morsche, R., Raijmakers, M. T. M., Roes, E. M., Peters, W. H. M., Steegers, E. A. P. Paternal contribution to the risk for pre-eclampsia. J. Med. Genet. 39: 44-45, 2002. [PubMed: 11826024] [Full Text: https://doi.org/10.1136/jmg.39.1.44]