Skip to main content
SpringerLink
Log in

Glutathione S-transferases and cytochrome P450 detoxifying enzyme distribution in human cerebral glioma

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Malignant astrocytomas are frequently resistant to cytotoxic chemotherapy. A possible mechanism of chemoresistance is drug inactivation within malignant astrocytes by detoxifying enzymes (glutathione transferases (GST) and cytochrome P450's). The aim of this study was to assess whether there was differential expression of these detoxifying enzymes in the central nervous system and any relationship to histological grade (WHO) of the tumours.

Immunostaining was performed in 30 consecutive glioma samples, using class specific polyclonal antibodies to subtypes of GST (pi, alpha, mu) and to human cytochrome P450 reductase.

GST immunostaining was evident in astrocytes and endothelium but not neurones or oligodendrocytes in normal brain. Immunostaining for GST increased in intensity from well differentiated tumours to glioblastoma. Staining was least evident in surrounding normal brain, strong in reactive astrocytes and astrocytic tumour cells and very intense in gemistocytic and giant tumour cells. Small anaplastic tumour cells had very little GST staining. Where endothelial proliferation was evident, GST staining in endothelial cells was increased. Pi was always the predominant subclass, although GST alpha and mu were also expressed in some tumours. Cytochrome P450 reductase immunostaining was present in normal neurones and malignant astrocytes.

Gemistocytic astrocytic tumour cells stained intensely. Further work is necessary to see if there is any correlation between immunostaining intensity survival or response to chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hayes JD, Wolf CR: Molecular mechanisms of drug resistance. Biochemical Journal 272: 1–15, 1990

    PubMed  Google Scholar 

  2. Wolf CR, Wareing CJ, Black SM, Hayes JD: Glutathione S-transferases in resistance to chemotherapeutic drugs. In: Hayes JD, Pickett CB, Mantle TJ (eds) Glutathione S-transferases and Drug Resistance, pp 296–307. Taylor and Francis, London

  3. Becker I, Becker K-F, Meyermann R, Holt V: The multidrug resistance gene MDR1 is expressed in human glial tumors. Acta Neuropathol 82: 516–519, 1991

    PubMed  Google Scholar 

  4. Smith MT, Evans CG, Doane-Setzer P, Castro VM, Tahir MK, Mannervik B: Denitrosation of 1,3-Bis(2-chloroethyl)-1-nitrosourea by class mu glutathione transferases and its role in cellular resistance in rat brain tumor cells. Cancer Res 49: 2621–2625, 1989

    PubMed  Google Scholar 

  5. Hayes JD, Wolf CR: The role of glutathione transferase in drug resistance. In: Seis H, Ketterer B (eds) Glutathione Conjugation: Mechanisms and Biological Significance, pp 316–355. Academic Press, London

  6. Black SM, Wolf CR: The role of glutathione-dependent enzymes in drug resistance. Pharmac Ther 51: 139–154, 1991

    Google Scholar 

  7. Ali-Osman F, Caughlin J, Gray GS: Decreased DNA interstrand crosslinking and cytotoxicity induced in human brain tumor cells by 1,3-Bis(2-chloroethyl)-1-nitrosourea afterin vitro reaction with glutathione. Cancer Res 49: 5954–5959, 1989

    PubMed  Google Scholar 

  8. Carder PJ, Hume R, Fryer AA, Strange RC, Lauder J, Bell JE: Glutathione S-transferase in human brain. Neuropath Appl Neurobiol 16: 293–303, 1990

    Google Scholar 

  9. Strange RC, Fryer AA, Matharoo B, Zhao L, Broome J, Campbell A, Jones P, Pastor IC Singh RVP: The human Glutathione S-transferases: Comparison of isoenzyme expression in normal and astrocytoma brain. Biochem Biophys Acta 1139(3): 222–228, 1992

    PubMed  Google Scholar 

  10. World Health Organization International Classification of Tumours: Histological typing of tumours of the central nervous system. In: Kleihues P, Burger PC, Scheithauer BW (eds) Second Edition. Springer Verlag, Berlin 1993

    Google Scholar 

  11. Yung WKA, Levin VA: Chemotherapy: Current and future role and expectations. In: Apuzzo MLJ (ed) Neurosurgical Topics: Malignant Cerebral Glioma. American Association of Neurological Surgeons: Park Ridge, Illinois, USA

  12. Grant R, Liang B, Page M, Greenberg H, Junck L: Age influences chemotherapy response in glioma, irrespective of tumor grade. Ann Neurol 32(2): 289–290, 1992

    Google Scholar 

  13. Kara A, Yamada H, Sakai N, Hirayama H, Tanaka T, Mori H: Immunohistochemical demonstration of the placental form of glutathione S-transferase, a detoxifying enzyme in human gliomas. Cancer 66: 2563–2568, 1990

    PubMed  Google Scholar 

  14. Evans CG, Bodell WJ, Tokuda K, Doane-Setzer P, Smith MT: Glutathione and related enzymes in rat brain tumor cell resistance to 1,3,Bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard. Cancer Res 49: 2523–2530, 1989

    Google Scholar 

  15. Hill DR: N,N′-bis(2-chloroethyl)-N-nitrosourea, a substrate for glutathione S-transferase. Proc Am Assoc Cancer Res 17: 52, 1976

    Google Scholar 

  16. Castro VM: Significance of glutathione transferases in the resistance of tumor cells to alkylating cytostatic drugs. Doctorial dissertation Stockholm 1991, Department of Biochemistry, Stockholm University. ISBN 91-7146 876-5. Akademitryck AB, Edsbruk 1991

    Google Scholar 

  17. Yang WZ, Begleiter A, Johnstone JB, Israels LG, Mowat MR: Role of glutathione and glutathione S-transferase in chlorambucil resistance. Mol Pharmacol 41(4): 625–630, 1992

    PubMed  Google Scholar 

  18. Peters WH, Roelofs HM: Biochemical characterization of resistance to mitoxantrone and adriamycin in caco-2 human colon adenocarcinoma cells: a possible role for glutathione S-transferase. Cancer Res 52(7): 1886–1890, 1992

    PubMed  Google Scholar 

  19. Sato K, Kitahara A, Satoh K, Ishikawa T, Tatematsu M, Ito N: The placental form of glutathione s-transferase as a new marker protein for pre-neoplasia in rat chemical hepatocarcinomatosis. Cancer Research 44: 2698–2703, 1984

    PubMed  Google Scholar 

  20. Shiratori Y, Soma Y, Maruyama H, Sato S, Takano A, Sato K: Immunohistochemical detection of the placental form of glutathione s-transferase in dysplastic and neoplastic human uterine cervix lesions. Cancer Research 47: 6806–6809, 1987

    PubMed  Google Scholar 

  21. Smith MT, Evans CG, Doane-Setzer P, Castro VM, Tahir MK, Mannervik B: Denitrosation of 1,3-Bis(2-chloroethyl)-1-nitrosourea by class mu glutathione transferases and its role in cellular resistance in rat brain tumor cells. Cancer Res 49: 2621–2625, 1989

    PubMed  Google Scholar 

  22. Hercbergs A, Brok-Simoni F, Holtzman F, Bar-Am J, Leith JT, Brenner JH: Erythrocyte glutathione and tumour response to chemotherapy. Lancet 339(8801): 1074–1076, 1992

    PubMed  Google Scholar 

  23. Beckett GJ, Howie AF, Hussey AJ, Hayes PC, Miller WR, Hayes JD: Radioimmunoassay measurements of the human glutathione S-transferases. In: Hayes JD, Pickett CB, Mantle TJ (eds) Glutathione S-transferases and drug resistance. 1990: p 309. Taylor and Francis, London

    Google Scholar 

  24. Strange RC, Faulder CG, Davis BA, Hume R, Brown JAH, Cotton W, Hopkinson DA: The human glutathione S transferases: studies on the distribution and genetic variation of GST-1, GST-2, and GST-3 isoenzymes. Ann Hum Genet 48: 11–20, 1984

    PubMed  Google Scholar 

  25. Hussey AJ, Hayes JD, Beckett GJ: Measurement of human neutral glutathione S transferase (GST) concentrations in plasma and biopsy tissue using radioimmunoassay. Biochem Pharmacop 36: 4013–1015, 1987

    Google Scholar 

  26. Seidegard J, Pero RW, Miller DG, Beattie EJ: A glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer. Carcinogenesis 7: 751–753, 1986

    PubMed  Google Scholar 

  27. Seidegard J, Pero RW, Markowitz MM, Roush G, Miller DG, Beattie EJ: Isozyme(s) of glutathione transferase (class mu) as a marker for the susceptibility to lung cancer: a follow-up study. Carcinogenesis 11: 33–36, 1990

    PubMed  Google Scholar 

  28. Warner M, Ahlgren R, Zaphiropoulos PG, Hayashi S-I, Gustafsson J-A. In: Methods in Enzymology: Identification of P450s in the brain. 206: 631–640, 1991

    Google Scholar 

  29. Walther B, Ghersi-Egea JF, Minn A, Siest G: Subcellular distribution of cytochrome P-450 in the brain. Brain Res 375: 338–344, 1986

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK

    Robert Grant

  2. Neuropathology Laboratory, University Department of Pathology, Western General Hospital, Edinburgh, UK

    James W. Ironside

Authors
  1. Robert Grant
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James W. Ironside
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grant, R., Ironside, J.W. Glutathione S-transferases and cytochrome P450 detoxifying enzyme distribution in human cerebral glioma. J Neuro-Oncol 25, 1–7 (1995). https://doi.org/10.1007/BF01054717

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01054717

Key words

Search

Navigation