Thiopurine toxicity to ...; Deficiency thiopurine S-methyltransferase (thiopurine S-methyltransferase deficiency -TPMT-) - Gen TPMT

Thiopurines both azathioprine (AZA) and its derivative, 6-mercaptourine (6-MP), play a very important role as immunosuppressants or cytotoxic agents used in the treatment of autoimmune, hematological neoplasias diseases and to prevent rejection in organ transplants. AZA is a prodrug that is converted to 6-MP in vivo. 6-MP, in turn, is also a prodrug that undergoes a series of changes to form active metabolites which are incorporated into DNA, called nucleotides thioguanines (6-TGNs). For inactivation two types of reactions, catalyzed by xanthine oxidase and other catalyzed by thiopurine S-methyltransferase (TPMT) may occur. The latter (TPMT) catalyzes an S-methylation. In the absence of xanthine oxidase hematopoietic level, TMPT is primarily responsible for metabolizing thiopurines.

The existence of various allelic variants in the TPMT gene, located on the short arm of chromosome 6 (6p22.3), is expressed by the presence of multiple phenotypes of TPMT enzyme, that differ in their ability to methylate AZA and 6- MP. This involves differences in metabolism thiopurines, varying their bioavailability and activity level of patient to patient, increasing the risks of adverse effects, among which myelosuppression and leukopenia, when used for all the same dosage based solely on the patient 's weight, adjusted side effects arising. Instead, through genetic the TPMT gene could be used depends on the metabolic capacity of TPMT, predictable by genotype and presence or absence of genetic variations in TPMT gene.

So far they have been detected more than 40 allelic variants for TPMT gene, as a result of differences in regions that control enzyme activity. TPMT * 1 variant, corresponding to the presence of two wild type alleles, and is the most common phenotype is associated with high enzymatic activity. All other variants, alleles that result in a TPMTs with reduced activity, ie, with a decreased capacity for the S-methylation of AZA / 6-MP capacity, and its conversion into active metabolites (6-TGNs correspond ). The accumulation of AZA or 6-MP produces an increase in adverse effects such as nausea, leukopenia, myelosuppression, elevated transaminases, or other liver dysfunction.

There are many allelic variants of TPMT, but more than 95% of published cases are individuals with allelic variants TPMT * 2, TPMT * 3A and TPMT * 3C. If homozygotes, TPMT * 2 variant decreases its enzymatic activity 100 times compared to non - mutated variant (TPMT * 1), while TPMT * 3 A completely lost its enzymatic activity. Heterozygotes have intermediate activity, since TPMT gene alleles are inherited codominant. Other allelic variants were occasionally found, or only in certain population groups.

The study of TPMT gene can be performed to detect only the allelic variant unmutated (TPMT * 1) together with the most common allelic variants mutated ((TPMT * 2, TPMT * 3A and TPMT * 3C) or sequencing all exons gene, which can be detected any allelic variant.

TPMT activity enzyme is inherited in an autosomal codominant. Codominance means that two different versions of the gene are expressed, and both versions influence the genetic trait. TPMT gene can be classified as low activity or high activity. When the gene is altered in a way that affects the activity of the enzyme TPMT, it described as low activity. When the gene is altered and TPMT activity is normal, it is described as high activity. Since two copies of the gene are present in each cell, each person may have two copies of low activity, a low - copy and a copy activity high activity, or two copies of high activity. Those with two copies of low TPMT activity in each cell gene are deficient in TPMT and are at increased risk of developing hematopoietic toxicity when treated with thiopurine drugs unless they receive a dose much lower than usual. People with a copy of high activity and low activity back have moderately reduced enzymatic activity and are also at greater risk of this complication unless it receives a significantly lower dose of the drug. Those with two copies of high activity have normal TPMT activity and have a higher risk of hematopoietic toxicity with thiopurine drug treatment.

Tests in IVAMI: in IVAMI can perform the study according to the two guidelines: detecting the most frequent variants, or perform the complete sequencing of all exons of TPMT gene, to detect any allelic variant may alter the enzymatic activity of thiopurine S methyltransferase (TPMT).

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).