Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms.
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 allele 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 bold the promise of improving the safety and efficacy of thiopurine therapy.
Krynetski
E Y
EY
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Tai
H L
HL
Yates
C R
CR
Fessing
M Y
MY
Loennechen
T
T
Schuetz
J D
JD
Relling
M V
MV
Evans
W E
WE
D000483:Alleles; D006801:Humans; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011110:Polymorphism, Genetic
D008780:Methyltransferases; C022745:thiopurine methyltransferase