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. 1995 Apr;39(4):411–415. doi: 10.1111/j.1365-2125.1995.tb04470.x

Glutathione S-transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis.

V J Green 1, M Pirmohamed 1, N R Kitteringham 1, M J Knapp 1, B K Park 1
PMCID: PMC1365129  PMID: 7640148

Abstract

1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine) which is used in Alzheimer's disease, causes elevation of liver transaminases ('tacrine transaminitis') in 40-50% of patients. This may be related to the formation of a chemically reactive metabolite from tacrine, which can be detoxified in vitro by glutathione. 2. Glutathione-S-transferase mu (GSTM1), a detoxication enzyme, is polymorphically expressed being absent in about 50% of patients. Its role in the detoxication of the reactive metabolite of tacrine is not known. 3. The frequency of the enzyme deficiency (GSTM1*0) has been investigated in patients with tacrine transaminitis using polymerase chain reaction (PCR) to determine whether the GSTM1 status can be used as an absolute predictive factor for susceptibility to tacrine transaminitis. 4. The frequency of the GSTM1*0 genotype in patients with tacrine transaminitis (n = 33; 45.5%) was not significantly different from that in patients treated with tacrine without liver dysfunction (n = 37; 43%), and when compared with all the controls used in the study (n = 167; 56%). 5. The frequency of the GSTM1*0 genotype in patients with Alzheimer's disease (n = 79; 46%) was not significantly different from that in healthy volunteers (n = 121; 59.5%). 6. Our results indicate that the GSTM1 status cannot be used clinically to predict individual susceptibility to tacrine transaminitis, and that patients with the GSTM1*0 genotype are unlikely to have an increased risk of tacrine-induced liver damage. Furthermore, the GSTM1 status was not associated with Alzheimer's disease.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bell D. A., Taylor J. A., Paulson D. F., Robertson C. N., Mohler J. L., Lucier G. W. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J Natl Cancer Inst. 1993 Jul 21;85(14):1159–1164. doi: 10.1093/jnci/85.14.1159. [DOI] [PubMed] [Google Scholar]
  2. Bell D. A., Thompson C. L., Taylor J., Miller C. R., Perera F., Hsieh L. L., Lucier G. W. Genetic monitoring of human polymorphic cancer susceptibility genes by polymerase chain reaction: application to glutathione transferase mu. Environ Health Perspect. 1992 Nov;98:113–117. doi: 10.1289/ehp.9298113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boyer T. D. The glutathione S-transferases: an update. Hepatology. 1989 Mar;9(3):486–496. doi: 10.1002/hep.1840090324. [DOI] [PubMed] [Google Scholar]
  4. Brockmöller J., Gross D., Kerb R., Drakoulis N., Roots I. Correlation between trans-stilbene oxide-glutathione conjugation activity and the deletion mutation in the glutathione S-transferase class mu gene detected by polymerase chain reaction. Biochem Pharmacol. 1992 Feb 4;43(3):647–650. doi: 10.1016/0006-2952(92)90591-6. [DOI] [PubMed] [Google Scholar]
  5. Comstock K. E., Johnson K. J., Rifenbery D., Henner W. D. Isolation and analysis of the gene and cDNA for a human Mu class glutathione S-transferase, GSTM4. J Biol Chem. 1993 Aug 15;268(23):16958–16965. [PubMed] [Google Scholar]
  6. Daly A. K., Thomas D. J., Cooper J., Pearson W. R., Neal D. E., Idle J. R. Homozygous deletion of gene for glutathione S-transferase M1 in bladder cancer. BMJ. 1993 Aug 21;307(6902):481–482. doi: 10.1136/bmj.307.6902.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Guengerich F. P., Liebler D. C. Enzymatic activation of chemicals to toxic metabolites. Crit Rev Toxicol. 1985;14(3):259–307. doi: 10.3109/10408448509037460. [DOI] [PubMed] [Google Scholar]
  9. Hajimohammadreza I., Brammer M. Brain membrane fluidity and lipid peroxidation in Alzheimer's disease. Neurosci Lett. 1990 May 4;112(2-3):333–337. doi: 10.1016/0304-3940(90)90226-y. [DOI] [PubMed] [Google Scholar]
  10. Idle J. R. Is environmental carcinogenesis modulated by host polymorphism? Mutat Res. 1991 Apr;247(2):259–266. doi: 10.1016/0027-5107(91)90021-f. [DOI] [PubMed] [Google Scholar]
  11. Jackson M. R., Craft J. A., Burchell B. Nucleotide and deduced amino acid sequence of human liver microsomal epoxide hydrolase. Nucleic Acids Res. 1987 Sep 11;15(17):7188–7188. doi: 10.1093/nar/15.17.7188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Knapp M. J., Knopman D. S., Solomon P. R., Pendlebury W. W., Davis C. S., Gracon S. I. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA. 1994 Apr 6;271(13):985–991. [PubMed] [Google Scholar]
  13. Madden S., Woolf T. F., Pool W. F., Park B. K. An investigation into the formation of stable, protein-reactive and cytotoxic metabolites from tacrine in vitro. Studies with human and rat liver microsomes. Biochem Pharmacol. 1993 Jul 6;46(1):13–20. doi: 10.1016/0006-2952(93)90342-t. [DOI] [PubMed] [Google Scholar]
  14. Mannervik B., Danielson U. H. Glutathione transferases--structure and catalytic activity. CRC Crit Rev Biochem. 1988;23(3):283–337. doi: 10.3109/10409238809088226. [DOI] [PubMed] [Google Scholar]
  15. Nebert D. W. Role of genetics and drug metabolism in human cancer risk. Mutat Res. 1991 Apr;247(2):267–281. doi: 10.1016/0027-5107(91)90022-g. [DOI] [PubMed] [Google Scholar]
  16. O'Brien J. T., Eagger S., Levy R. Effects of tetrahydroaminoacridine on liver function in patients with Alzheimer's disease. Age Ageing. 1991 Mar;20(2):129–131. doi: 10.1093/ageing/20.2.129. [DOI] [PubMed] [Google Scholar]
  17. Park B. K., Pirmohamed M., Kitteringham N. R. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol. 1992 Nov;34(5):377–395. doi: 10.1111/j.1365-2125.1992.tb05647.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Reed D. J. Glutathione: toxicological implications. Annu Rev Pharmacol Toxicol. 1990;30:603–631. doi: 10.1146/annurev.pa.30.040190.003131. [DOI] [PubMed] [Google Scholar]
  19. Riley R. J., Cribb A. E., Spielberg S. P. Glutathione transferase mu deficiency is not a marker for predisposition to sulphonamide toxicity. Biochem Pharmacol. 1991 Jul 15;42(3):696–698. doi: 10.1016/0006-2952(91)90334-2. [DOI] [PubMed] [Google Scholar]
  20. Rozemuller J. M., Eikelenboom P., Stam F. C., Beyreuther K., Masters C. L. A4 protein in Alzheimer's disease: primary and secondary cellular events in extracellular amyloid deposition. J Neuropathol Exp Neurol. 1989 Nov;48(6):674–691. doi: 10.1097/00005072-198911000-00009. [DOI] [PubMed] [Google Scholar]
  21. Seidegård J., Pero R. W., Markowitz M. M., Roush G., Miller D. G., Beattie E. J. Isoenzyme(s) of glutathione transferase (class Mu) as a marker for the susceptibility to lung cancer: a follow up study. Carcinogenesis. 1990 Jan;11(1):33–36. doi: 10.1093/carcin/11.1.33. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Seidegård J., Pero R. W. The hereditary transmission of high glutathione transferase activity towards trans-stilbene oxide in human mononuclear leukocytes. Hum Genet. 1985;69(1):66–68. doi: 10.1007/BF00295531. [DOI] [PubMed] [Google Scholar]
  24. Seidegård J., Vorachek W. R., Pero R. W., Pearson W. R. Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7293–7297. doi: 10.1073/pnas.85.19.7293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Smith C. D., Carney J. M., Starke-Reed P. E., Oliver C. N., Stadtman E. R., Floyd R. A., Markesbery W. R. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10540–10543. doi: 10.1073/pnas.88.23.10540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Takahashi Y., Campbell E. A., Hirata Y., Takayama T., Listowsky I. A basis for differentiating among the multiple human Mu-glutathione S-transferases and molecular cloning of brain GSTM5. J Biol Chem. 1993 Apr 25;268(12):8893–8898. [PubMed] [Google Scholar]
  27. Tsuchida T., Hruban R. H., Carson B. S., Phillips P. C. Colloid cysts of the third ventricle: immunohistochemical evidence for nonneuroepithelial differentiation. Hum Pathol. 1992 Jul;23(7):811–816. doi: 10.1016/0046-8177(92)90352-4. [DOI] [PubMed] [Google Scholar]
  28. Volicer L., Crino P. B. Involvement of free radicals in dementia of the Alzheimer type: a hypothesis. Neurobiol Aging. 1990 Sep-Oct;11(5):567–571. doi: 10.1016/0197-4580(90)90119-k. [DOI] [PubMed] [Google Scholar]
  29. Watkins P. B., Zimmerman H. J., Knapp M. J., Gracon S. I., Lewis K. W. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA. 1994 Apr 6;271(13):992–998. [PubMed] [Google Scholar]
  30. Woolf T. F., Pool W. F., Bjorge S. M., Chang T., Goel O. P., Purchase C. F., 2nd, Schroeder M. C., Kunze K. L., Trager W. F. Bioactivation and irreversible binding of the cognition activator tacrine using human and rat liver microsomal preparations. Species difference. Drug Metab Dispos. 1993 Sep-Oct;21(5):874–882. [PubMed] [Google Scholar]
  31. Zaman Z., Roche S., Fielden P., Frost P. G., Niriella D. C., Cayley A. C. Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease. Age Ageing. 1992 Mar;21(2):91–94. doi: 10.1093/ageing/21.2.91. [DOI] [PubMed] [Google Scholar]

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