Pharmacogenetics of TPMT

Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes the S-methylation of thiopurine drugs to inactive, nontoxic metabolites. Thus far no natural substrate has been found for this enzyme. TPMT transcripts are expressed in various tissues, including lung, liver, skeletal muscle, kidney, and red and white blood cells. Several studies have established that single nucleotide polymorphisms (SNPs) in the TPMT gene leading to inactive enzyme are the major cause of hematopoietic toxicity due to thiopurine drugs.

There are three main enzymatic phenotypes of TPMT (low, medium, and high) that show a trimodal inheritance pattern. Eighty-nine percent of the population have normal to high TPMT activity representing two wildtype alleles, 11% have intermediate activity indicating heterozygosity for a TPMT mutant allele, and 1 in 300 (0.3%) have low or no TPMT activity and represent homozygous or compound heterozygotes for TPMT polymorphisms. There are at least 23 different TPMT alleles reported in the literature, with the wildtype designated as TPMT*1. At least 22 alleles have been associated with low or no TPMT activity, but 3 of these (TPMT*2, TPMT*3A, and TPMT*3C) account for 95% of the mutant alleles in the Caucasian, African-American, and Asian populations.2,4 There is a difference in variant allele frequencies among races. TPMT*3A is present in about 5% of the Caucasian population, and TPMT*3C is most common in Asian and African-American populations.

A large number of studies have been performed to evaluate the correlation between the TPMT genotype and its enzymatic activity/phenotype (Fig. 74.2). Both in vitro and in vivo characterization of TPMT activities of the most common mutants listed above demonstrate enhanced proteolysis of the variant proteins, thus reducing enzymatic activity. Several studies among different populations have demonstrated a >98% concordance between TPMT enzyme activity and genotype.1 Using the genotype to predict the TPMT phenotype yielded >90% sensitivity and >95% specificity.

TPMT genotype and activity also correlate with myelotoxicity. Several studies among different patient populations have demonstrated a skewed distribution of TPMT genotypes in patients experiencing thiopurine drug-induced toxicity. Whereas an unselected population has a TPMT variant rate of ~ 10%, 60-70% of patients who develop myelotoxicity have one or two mutant TPMT alleles.2

The proposed mechanism of toxicity of thiopurine drugs is through incorporation of drug metabolites, thioguanine nucleotides (TGN), into DNA and RNA, and many studies have demonstrated an association between higher TGN concentrations and mutant TPMT alleles.1,2 These data suggest that physicians can identify patients who are at increased risk for adverse drug reactions to thiopurine drugs by genotyping or phenotyping the TPMT gene or enzyme prior to prescribing the drug.

G enoty pe/Ph e noty pe

Drug Dose

Systemic Exposure


10 8

TPMT Allales


Conventional Dosing



•*2, "3A, *3C

L~'*wt/v> j

v/v //•^y

M. ■ X


Individualized Dosing

10 20 TPMT Activity

Individualized Dosing



5000 4000 3000 2000 1000 0

deficient wild-type heterozygote TPMT phenotype

5000 4000 3000 2000 1000 0

1 0,2 Ä 0, deficient wild-type heterozygote TPMT phenotype

1 1.5 Years

1 1.5 Years

Figure 74.2 Genetic polymorphism of thiopurine methyltransferase and its role in determining response to thiopurine medications (azathioprine, mercaptopurine, thioguanine). The left panels depict the predominant TPMT mutant alleles causing autosomal codominant inheritance of TPMT activity in humans. As depicted in the subsequent top three panels, when uniform (conventional) dosages of thiopurine medications are administered to all patients, TPMT-deficient patients accumulate markedly higher (10-fold) cellular concentrations of active thioguanine nucleotides (TGNs), and heterozygous patients accumulated about twofold higher TGN concentrations, translating into a significantly higher frequency of hematopoietic toxicity (far right panels). As depicted in the bottom three panels, when genotype-specific dosing of thiopurines is administered, comparable cellular TGN concentrations are achieved, and all three TPMT phenotypes can be treated without acute toxicity. (Reproduced with permission from Evans, W. E.: Thiopurine 5-methyl transferase: a genetic polymorphism that affects a small number of drugs in a big way. Pharmacogenetics i2(6):421-3, 2002).

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