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. 1994 Oct;49(10):1010–1014. doi: 10.1136/thx.49.10.1010

Heterogeneous expression and polymorphic genotype of glutathione S-transferases in human lung.

A M Cantlay 1, C A Smith 1, W A Wallace 1, P L Yap 1, D Lamb 1, D J Harrison 1
PMCID: PMC475239  PMID: 7974294

Abstract

BACKGROUND--Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics by conjugation with glutathione. One of the mu class genes of this superfamily of enzymes, GSTM1, is polymorphic because of a partial gene deletion. This results in a failure to express GSTM1 in approximately 50% of individuals. Several studies have linked GSTM1 null status to an increased risk of lung carcinoma. This study investigated the expression and distribution of GST isoenzymes in human lung, and developed a polymerase chain reaction (PCR) assay which would allow genotyping of archival, paraffin embedded lung tissue. METHODS--Distribution was examined using a panel of polyclonal anti-GST antibodies for immunohistochemistry in normal tissue of 21 tumour-bearing lungs. DNA for PCR was extracted from paraffin blocks and a control group of 350 blood lysates. As a positive control each assay amplified part of GSTM4, a mu class gene which is not polymorphic but which shows strong sequence homology to GSTM1. The presence of GST in bronchoalveolar lavage fluid was sought by Western analysis. RESULTS--Proximal airways contained pi class GST, alpha class GST, and mu class GST with expression concentrated in the brush border. In distal airspaces no alpha GST was expressed but pi GST and mu GST were present in alveolar cells and also alveolar macrophages. Pi class GST was present in bronchoalveolar lavage fluid. The PCR assay enabled genotypic determination using DNA extracted from archival material. Of the control group 56% were null at the GSTM1 locus. CONCLUSIONS--The distribution of GST isoenzymes in the lung is heterogeneous with an apparent decrease in GST in distal lung. Since GSTM1 status has already been associated with susceptibility to disease, the PCR assay developed will allow further studies of the relation between genotype and structural disorders in the lung using archival pathological material.

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Selected References

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  1. Anttila S., Hirvonen A., Vainio H., Husgafvel-Pursiainen K., Hayes J. D., Ketterer B. Immunohistochemical localization of glutathione S-transferases in human lung. Cancer Res. 1993 Dec 1;53(23):5643–5648. [PubMed] [Google Scholar]
  2. Awasthi Y. C., Singh S. V., Ahmad H., Moller P. C. Immunocytochemical evidence for the expression of GST1, GST2, and GST3 gene loci for glutathione S-transferase in human lung. Lung. 1987;165(6):323–332. doi: 10.1007/BF02714448. [DOI] [PubMed] [Google Scholar]
  3. Carmichael J., Forrester L. M., Lewis A. D., Hayes J. D., Hayes P. C., Wolf C. R. Glutathione S-transferase isoenzymes and glutathione peroxidase activity in normal and tumour samples from human lung. Carcinogenesis. 1988 Sep;9(9):1617–1621. doi: 10.1093/carcin/9.9.1617. [DOI] [PubMed] [Google Scholar]
  4. Cossar D., Bell J., Strange R., Jones M., Sandison A., Hume R. The alpha and pi isoenzymes of glutathione S-transferase in human fetal lung: in utero ontogeny compared with differentiation in lung organ culture. Biochim Biophys Acta. 1990 Feb 9;1037(2):221–226. doi: 10.1016/0167-4838(90)90171-b. [DOI] [PubMed] [Google Scholar]
  5. Coursin D. B., Cihla H. P., Oberley T. D., Oberley L. W. Immunolocalization of antioxidant enzymes and isozymes of glutathione S-transferase in normal rat lung. Am J Physiol. 1992 Dec;263(6 Pt 1):L679–L691. doi: 10.1152/ajplung.1992.263.6.L679. [DOI] [PubMed] [Google Scholar]
  6. Faulder C. G., Hirrell P. A., Hume R., Strange R. C. Studies of the development of basic, neutral and acidic isoenzymes of glutathione S-transferase in human liver, adrenal, kidney and spleen. Biochem J. 1987 Jan 1;241(1):221–228. doi: 10.1042/bj2410221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fryer A. A., Hume R., Strange R. C. The development of glutathione S-transferase and glutathione peroxidase activities in human lung. Biochim Biophys Acta. 1986 Oct 1;883(3):448–453. doi: 10.1016/0304-4165(86)90283-7. [DOI] [PubMed] [Google Scholar]
  8. Fryer A. A., Zhao L., Alldersea J., Boggild M. D., Perrett C. W., Clayton R. N., Jones P. W., Strange R. C. The glutathione S-transferases: polymerase chain reaction studies on the frequency of the GSTM1 0 genotype in patients with pituitary adenomas. Carcinogenesis. 1993 Apr;14(4):563–566. doi: 10.1093/carcin/14.4.563. [DOI] [PubMed] [Google Scholar]
  9. Harrison D. J., Kharbanda R., Cunningham D. S., McLellan L. I., Hayes J. D. Distribution of glutathione S-transferase isoenzymes in human kidney: basis for possible markers of renal injury. J Clin Pathol. 1989 Jun;42(6):624–628. doi: 10.1136/jcp.42.6.624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hayashi S., Watanabe J., Kawajiri K. High susceptibility to lung cancer analyzed in terms of combined genotypes of P450IA1 and Mu-class glutathione S-transferase genes. Jpn J Cancer Res. 1992 Aug;83(8):866–870. doi: 10.1111/j.1349-7006.1992.tb01992.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Howie A. F., Bell D., Hayes P. C., Hayes J. D., Beckett G. J. Glutathione S-transferase isoenzymes in human bronchoalveolar lavage: a possible early marker for the detection of lung cancer. Carcinogenesis. 1990 Feb;11(2):295–300. doi: 10.1093/carcin/11.2.295. [DOI] [PubMed] [Google Scholar]
  12. Jackson D. P., Lewis F. A., Taylor G. R., Boylston A. W., Quirke P. Tissue extraction of DNA and RNA and analysis by the polymerase chain reaction. J Clin Pathol. 1990 Jun;43(6):499–504. doi: 10.1136/jcp.43.6.499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ketterer B., Harris J. M., Talaska G., Meyer D. J., Pemble S. E., Taylor J. B., Lang N. P., Kadlubar F. F. The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer. Environ Health Perspect. 1992 Nov;98:87–94. doi: 10.1289/ehp.929887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mannervik B., Awasthi Y. C., Board P. G., Hayes J. D., Di Ilio C., Ketterer B., Listowsky I., Morgenstern R., Muramatsu M., Pearson W. R. Nomenclature for human glutathione transferases. Biochem J. 1992 Feb 15;282(Pt 1):305–306. doi: 10.1042/bj2820305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McLellan L. I., Harrison D. J., Hayes J. D. Modulation of glutathione S-transferases and glutathione peroxidase by the anticarcinogen butylated hydroxyanisole in murine extrahepatic organs. Carcinogenesis. 1992 Dec;13(12):2255–2261. doi: 10.1093/carcin/13.12.2255. [DOI] [PubMed] [Google Scholar]
  16. Petruzzelli S., Bernard P., Paoletti P., Rane A., Giuntini C., Pacifici G. M. Presence of epoxide hydrolase and glutathione S-transferase in human pulmonary alveolar macrophages. Eur J Clin Pharmacol. 1988;34(4):419–421. doi: 10.1007/BF00542447. [DOI] [PubMed] [Google Scholar]
  17. Seidegård J., Pero R. W., Miller D. G., Beattie E. J. A glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer. Carcinogenesis. 1986 May;7(5):751–753. doi: 10.1093/carcin/7.5.751. [DOI] [PubMed] [Google Scholar]
  18. Shea T. C., Claflin G., Comstock K. E., Sanderson B. J., Burstein N. A., Keenan E. J., Mannervik B., Henner W. D. Glutathione transferase activity and isoenzyme composition in primary human breast cancers. Cancer Res. 1990 Nov 1;50(21):6848–6853. [PubMed] [Google Scholar]
  19. Shimizu T. Enzymes functional in the syntheses of leukotrienes and related compounds. Int J Biochem. 1988;20(7):661–666. doi: 10.1016/0020-711x(88)90160-7. [DOI] [PubMed] [Google Scholar]
  20. Smith C. A., Moss J. E., Gough A. C., Spurr N. K., Wolf C. R. Molecular genetic analysis of the cytochrome P450-debrisoquine hydroxylase locus and association with cancer susceptibility. Environ Health Perspect. 1992 Nov;98:107–112. doi: 10.1289/ehp.9298107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Zhong S., Spurr N. K., Hayes J. D., Wolf C. R. Deduced amino acid sequence, gene structure and chromosomal location of a novel human class Mu glutathione S-transferase, GSTM4. Biochem J. 1993 Apr 1;291(Pt 1):41–50. doi: 10.1042/bj2910041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Zhong S., Wyllie A. H., Barnes D., Wolf C. R., Spurr N. K. Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis. 1993 Sep;14(9):1821–1824. doi: 10.1093/carcin/14.9.1821. [DOI] [PubMed] [Google Scholar]
  23. van Poppel G., de Vogel N., van Balderen P. J., Kok F. J. Increased cytogenetic damage in smokers deficient in glutathione S-transferase isozyme mu. Carcinogenesis. 1992 Feb;13(2):303–305. doi: 10.1093/carcin/13.2.303. [DOI] [PubMed] [Google Scholar]

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