An antileukemic agent prescribed for pediatric oncology patients during the maintenance phase of therapy for acute lymphoblastic leukemia, 6-mercaptopurine (6-MP), is highly influenced by genetic variations in the thiopurine S-methyltransferase enzyme. As such, 6-MP must be dosed so that patients with 1 or 2 inactive thiopurine S-methyltransferase alleles will not incur an increased risk for my...

Most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications, these interindividual differences result in part from polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and/or drug targets (eg, receptors, enzymes). Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis of differences in drug efficacy ...

Escherichia coli cells expressing the tpm gene encoding the bacterial thiopurine methyltransferase (bTPMT) are shown to methylate selenite and (methyl)selenocysteine into dimethylselenide (DMSe) and dimethyldiselenide (DMDSe). E. coli cells expressing tpm from a gene library cosmid clone (harboring a Pseudomonas syringae insert of about 20 kb) also methylated selenate into DMSe and DMDSe. bTPMT...

Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% ...

PURPOSE Thiopurine drugs are well established treatments in the management of inflammatory bowel disease (IBD), but their use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in thiopurine metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating thiopurine therapy. Alt...

The activity of the enzyme thiopurine methyltransferase (TPMT) is regulated by a common genetic polymorphism. One in 300 individuals lack enzyme activity and 11% are heterozygous for a variant low activity allele and have an intermediate activity. The thiopurine drugs azathioprine, mercaptopurine and thioguanine are substrates for TPMT; these drugs exhibit well documented myelosuppressive effec...

The thiopurines azathioprine, mercaptopurine, and thioguanine are prodrugs that are converted to active thioguanine nucleotide metabolites or methylated by thiopurine methyltransferase (TPMT) to compounds with less pharmacologic activity. In the absence of TPMT activity, patients are likely to have higher concentrations of thioguanine nucleotides, which can pose an increased risk of severe life...

Thiopurine drugs are used to treat patients with neoplasia and autoimmune disease as well as transplant recipients. These agents are metabolized, in part, by S-methylation catalyzed by thiopurine methyltransferase (TPMT). The discovery nearly two decades ago that levels of TPMT activity in human tissues are controlled by a common genetic polymorphism led to one of the best examples of the poten...