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Gene Review

GSTM3  -  glutathione S-transferase mu 3 (brain)

Homo sapiens

Synonyms: GST class-mu 3, GST5, GSTB, GSTM3-3, GTM3, ...
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Disease relevance of GSTM3

  • No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity [1].
  • Of the putatively risk genotypes, GSTM3 AA, previously associated with susceptibility to skin cancer, was higher in the cases (odds ratio = 1.6, 95% CI 1.1-2.4) [2].
  • In contrast, the frequency of GSTM1 *B/*0 or *B/*B combined with GSTM3 *A/*A was significantly lower in patients with distal colorectal cancer, especially in males (OR = 0.37; 95% CI = 0.15-0.92) [3].
  • The putatively protective GSTM3 BB genotype was lower in patients with glottic (1.0%) than supraglottic (3.0%) squamous cell carcinoma [2].
  • The results suggest that expression of GSTM3 may play a role in determining prognosis in childhood ALL and could provide more information for accurate stratification of treatment [4].

Psychiatry related information on GSTM3


High impact information on GSTM3

  • To investigate the mechanism of GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype [6].
  • In this pedigree, the two children homozygous for the -63C/C genotype had 8-fold lower GSTM3 expression relative to the two children with the -63A/A genotype, with no association between A-783G SNP and GSTM3 expression [6].
  • These results show that the GSTM3 -63C allele strongly affects gene expression in human cell lines and suggests that individuals who carry the low expression allele may be deficient in glutathione transferase catalyzed biological functions [6].
  • Further evaluation using genotyped glioma cell lines and with luciferase reporter constructs showed that the -63C allele was associated with lower GSTM3 expression (P < 0.0001 and P < 0.003) [6].
  • Promoter sequencing revealed two novel GSTM3 promoter SNPs: A/C and A/G SNPs, 63 and 783 bp upstream of the codon 1 start site, respectively [6].

Chemical compound and disease context of GSTM3

  • We conclude, first, that mu class glutathione S-transferase influence risk of upper aerodigestive tract cancers thereby complementing studies in skin cancer patients showing GSTM1 A/B is protective, while GSTM3 AA moderately increases risk [2].

Biological context of GSTM3


Anatomical context of GSTM3

  • The staining for GSTM3 varied from minimal to very intense between individuals; in the bronchial epithelium, it was more abundant in current smokers than in exsmokers [11].
  • GSTM2, a striated muscle-specific isozyme, occurred minimally in the epithelium of the terminal airways, and GSTM3, an enzyme of broad extrahepatic occurrence, was observable in the ciliated airway epithelium and smooth muscle of the lung [11].
  • Only testis and brain were rich sources of GSTM3 subunits [12].
  • Immunohistochemical studies using a GSTM3-specific antiserum identified expression of the GSTM3 subunit in astrocytes [13].
  • The relative levels of expression of GSTM1 and GSTM3 in brain cytosols were determined after resolution of these enzymes using chromatofocusing [13].

Associations of GSTM3 with chemical compounds

  • Other polymorphic glutathione S-transferases include GSTM3, GSTP1, and GSTT1 [14].
  • Michaelis-Menten constants and turnover numbers for PGH2 were 141 microM and 10.8 min(-1) for GSTM2-2 and 1.5 mM and 130 min(-1) for GSTM3-3, respectively [15].
  • To study gene-gene interactions, a combined risk of gallbladder cancer due to ile/val or val/val were calculated in combination with null alleles of GSTM1 and GSTT1 or the *B allele of GSTM3, but there was no enhancement of risk [16].
  • Because hGSTM3 is rich in cysteine residues and readily undergoes S-glutathiolation reactions, deposition of this protein could originate from cross-links produced by oxidative stress [5].
  • CONCLUSION: These functional polymorphisms may play a significant role in modulating the ability of GSTM3-3 to metabolize substrates such as the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea [17].

Other interactions of GSTM3

  • Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95% CI = 1.73-7.36) [3].
  • Lymphoblast expression of GSTM3 was positively related to good prognosis whereas expression of GSTM4 was not related to clinical outcome in this small cohort [4].
  • CONCLUSIONS: These data provide the first evidence suggesting that polymorphism of the GSTM3 gene contributes to clinical severity in CF, which may have prognostic significance and could prompt to start a more targeted therapy in young patients with CF [18].
  • This showed, after correction for male gender and age, that GSTM3 AA was not associated with risk of increased numbers of tumors, although in combination with skin type 1, GSTM1 null, and CYP1A1 m1m1, the genotype did confer increased risk (P < 0.001, rate ratio, 2.058; P < 0.001, rate ratio, 1.606; P < 0.001, rate ratio, 1.470 respectively) [19].
  • Moreover, a positive interaction was found between mEH activity and GSTM3 genotype for laryngeal cancer [20].

Analytical, diagnostic and therapeutic context of GSTM3


  1. Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Tran, A., Jullien, V., Alexandre, J., Rey, E., Rabillon, F., Girre, V., Dieras, V., Pons, G., Goldwasser, F., Tréluyer, J.M. Clin. Pharmacol. Ther. (2006) [Pubmed]
  2. Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: studies in upper aerodigestive tract cancers. Matthias, C., Bockmühl, U., Jahnke, V., Jones, P.W., Hayes, J.D., Alldersea, J., Gilford, J., Bailey, L., Bath, J., Worrall, S.F., Hand, P., Fryer, A.A., Strange, R.C. Pharmacogenetics (1998) [Pubmed]
  3. Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor. Loktionov, A., Watson, M.A., Gunter, M., Stebbings, W.S., Speakman, C.T., Bingham, S.A. Carcinogenesis (2001) [Pubmed]
  4. Mu class glutathione S-transferase mRNA isoform expression in acute lymphoblastic leukaemia. Kearns, P.R., Chrzanowska-Lightowlers, Z.M., Pieters, R., Veerman, A., Hall, A.G. Br. J. Haematol. (2003) [Pubmed]
  5. Glutathione S-transferase hGSTM3 and ageing-associated neurodegeneration: relationship to Alzheimer's disease. Tchaikovskaya, T., Fraifeld, V., Urphanishvili, T., Andorfer, J.H., Davies, P., Listowsky, I. Mech. Ageing Dev. (2005) [Pubmed]
  6. Expression-based discovery of variation in the human glutathione S-transferase M3 promoter and functional analysis in a glioma cell line using allele-specific chromatin immunoprecipitation. Liu, X., Campbell, M.R., Pittman, G.S., Faulkner, E.C., Watson, M.A., Bell, D.A. Cancer Res. (2005) [Pubmed]
  7. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer. Saarikoski, S.T., Voho, A., Reinikainen, M., Anttila, S., Karjalainen, A., Malaveille, C., Vainio, H., Husgafvel-Pursiainen, K., Hirvonen, A. Int. J. Cancer (1998) [Pubmed]
  8. Metabolic susceptibility genes and prostate cancer risk in a southern European population: the role of glutathione S-transferases GSTM1, GSTM3, and GSTT1 genetic polymorphisms. Medeiros, R., Vasconcelos, A., Costa, S., Pinto, D., Ferreira, P., Lobo, F., Morais, A., Oliveira, J., Lopes, C. Prostate (2004) [Pubmed]
  9. Distinctive structure of the human GSTM3 gene-inverted orientation relative to the mu class glutathione transferase gene cluster. Patskovsky, Y.V., Huang, M.Q., Takayama, T., Listowsky, I., Pearson, W.R. Arch. Biochem. Biophys. (1999) [Pubmed]
  10. Polymorphisms in the glutathione S-transferase mu cluster are associated with tumour progression and patient outcome in colorectal cancer. Holley, S.L., Rajagopal, R., Hoban, P.R., Deakin, M., Fawole, A.S., Elder, J.B., Elder, J., Smith, V., Strange, R.C., Fryer, A.A. Int. J. Oncol. (2006) [Pubmed]
  11. Immunohistochemical localization of glutathione S-transferases in human lung. Anttila, S., Hirvonen, A., Vainio, H., Husgafvel-Pursiainen, K., Hayes, J.D., Ketterer, B. Cancer Res. (1993) [Pubmed]
  12. Subunit diversity and tissue distribution of human glutathione S-transferases: interpretations based on electrospray ionization-MS and peptide sequence-specific antisera. Rowe, J.D., Nieves, E., Listowsky, I. Biochem. J. (1997) [Pubmed]
  13. Allelism at the glutathione S-transferase GSTM3 locus: interactions with GSTM1 and GSTT1 as risk factors for astrocytoma. Hand, P.A., Inskip, A., Gilford, J., Alldersea, J., Elexpuru-Camiruaga, J., Hayes, J.D., Jones, P.W., Strange, R.C., Fryer, A.A. Carcinogenesis (1996) [Pubmed]
  14. Genetic polymorphisms and chromosome damage. Norppa, H. International journal of hygiene and environmental health. (2001) [Pubmed]
  15. Identification of mu-class glutathione transferases M2-2 and M3-3 as cytosolic prostaglandin E synthases in the human brain. Beuckmann, C.T., Fujimori, K., Urade, Y., Hayaishi, O. Neurochem. Res. (2000) [Pubmed]
  16. Genetic polymorphisms in GSTM1, GSTT1, GSTP1, GSTM3 and the susceptibility to gallbladder cancer in North India. Pandey, S.N., Jain, M., Nigam, P., Choudhuri, G., Mittal, B. Biomarkers (2006) [Pubmed]
  17. Polymorphism of human mu class glutathione transferases. Tetlow, N., Robinson, A., Mantle, T., Board, P. Pharmacogenetics (2004) [Pubmed]
  18. Glutathione-S-transferase M1, M3, P1 and T1 polymorphisms and severity of lung disease in children with cystic fibrosis. Flamant, C., Henrion-Caude, A., Boëlle, P.Y., Brémont, F., Brouard, J., Delaisi, B., Duhamel, J.F., Marguet, C., Roussey, M., Miesch, M.C., Boulé, M., Strange, R.C., Clement, A. Pharmacogenetics (2004) [Pubmed]
  19. Polymorphism at the glutathione S-transferase locus GSTM3: interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma. Yengi, L., Inskip, A., Gilford, J., Alldersea, J., Bailey, L., Smith, A., Lear, J.T., Heagerty, A.H., Bowers, B., Hand, P., Hayes, J.D., Jones, P.W., Strange, R.C., Fryer, A.A. Cancer Res. (1996) [Pubmed]
  20. High-activity microsomal epoxide hydrolase genotypes and the risk of oral, pharynx, and larynx cancers. Jourenkova-Mironova, N., Mitrunen, K., Bouchardy, C., Dayer, P., Benhamou, S., Hirvonen, A. Cancer Res. (2000) [Pubmed]
  21. Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure. Piirilä, P., Wikman, H., Luukkonen, R., Kääriä, K., Rosenberg, C., Nordman, H., Norppa, H., Vainio, H., Hirvonen, A. Pharmacogenetics (2001) [Pubmed]
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