Genetic polymorphism of thiopurine S-methyltransferase

Clinical importance and molecular mechanisms

Eugene Y. Krynetski, Hung Liang Tai, Charles Yates, Michael Y. Fessing, Thrina Loennechen, John D. Schuetz, Mary V. Relling, William E. Evans

Research output: Contribution to journalReview article

236 Citations (Scopus)

Abstract

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurines such as mercaptopurine and thioguanine. TPMT activity exhibits genetic polymorphism with about 1 in 300 inheriting TPMT-deficiency as an autosomal recessive trait. If treated with standard dosages of thiopurines, TPMT-deficient patients accumulate excessive thioguanine nucleotides (TGN) in hematopoietic tissues, leading to severe hematopoietic toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10-15-fold lower dosage of these medications. The human gene encoding polymorphic TPMT has been cloned and characterized, and two mutant alleles have recently been isolated from TPMT-deficient and heterozygous patients (TPMT*2, TPMT*3), permitting development of PCR-based methods to identify TPMT-deficient and heterozygous patients prior to therapy. TPMT*3 is the predominant mutant allere in American whites, accounting for about 75% of mutations in this population ongoing studies aim to better define the influence of TPMT activity on thiopurine efficacy, to identify additional mutant alleles and determine their frequency in different ethnic groups, to elucidate the mechanism(s) for loss of function of mutant proteins, to identify potential endogenous substrates and to define the molecular mechanisms of TPMT regulation. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy.

Original languageEnglish (US)
Pages (from-to)279-290
Number of pages12
JournalPharmacogenetics
Volume6
Issue number4
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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thiopurine methyltransferase
Genetic Polymorphisms
Thioguanine
Alleles
6-Mercaptopurine

All Science Journal Classification (ASJC) codes

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Krynetski, E. Y., Tai, H. L., Yates, C., Fessing, M. Y., Loennechen, T., Schuetz, J. D., ... Evans, W. E. (1996). Genetic polymorphism of thiopurine S-methyltransferase: Clinical importance and molecular mechanisms. Pharmacogenetics, 6(4), 279-290. https://doi.org/10.1097/00008571-199608000-00001

Genetic polymorphism of thiopurine S-methyltransferase : Clinical importance and molecular mechanisms. / Krynetski, Eugene Y.; Tai, Hung Liang; Yates, Charles; Fessing, Michael Y.; Loennechen, Thrina; Schuetz, John D.; Relling, Mary V.; Evans, William E.

In: Pharmacogenetics, Vol. 6, No. 4, 01.01.1996, p. 279-290.

Research output: Contribution to journalReview article

Krynetski, EY, Tai, HL, Yates, C, Fessing, MY, Loennechen, T, Schuetz, JD, Relling, MV & Evans, WE 1996, 'Genetic polymorphism of thiopurine S-methyltransferase: Clinical importance and molecular mechanisms', Pharmacogenetics, vol. 6, no. 4, pp. 279-290. https://doi.org/10.1097/00008571-199608000-00001
Krynetski, Eugene Y. ; Tai, Hung Liang ; Yates, Charles ; Fessing, Michael Y. ; Loennechen, Thrina ; Schuetz, John D. ; Relling, Mary V. ; Evans, William E. / Genetic polymorphism of thiopurine S-methyltransferase : Clinical importance and molecular mechanisms. In: Pharmacogenetics. 1996 ; Vol. 6, No. 4. pp. 279-290.
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