The Importance of Thiopurine Methyltransferase Activity for the Use of Azathioprine in Transplant Recipients1

Chocair, Pedro Renato; Duley, John A.; Simmonds, H. Anne; Cameron, J S

doi:10.1097/00007890-199205000-00016

Cited by 163 publications

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“…Accordingly, 275 individuals (89.9%) were classified as high-activity phenotype, 30 (9.8%) as intermediate-activity and one individual (0.3%) as low-activity. A trimodal distribution of TPMT activity, with a cut-off point between high-and intermediate-activity estimated to correspond to 9.5 U, was previously reported for a sample of healthy, uremic and organ transplanted Brazilians [8]. In the latter study, TPMT genotyping was not performed.…”

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confidence: 71%

Thiopurine methyltransferase phenotypes and genotypes in Brazilians

2003

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The polymorphism of thiopurine methyltransferase (TPMT) was studied in 306 healthy Brazilians who were classed, on the basis of self-declared colour and ancestry, as Euroderived (n 81), Afro-derived (n 18) or having interethnic admixture (n 204). TPMT activity (range 0.17-25.93 U) displayed a trimodal distribution of high (> 11.3 U; 9% of individuals), intermediate (5-11.3 U; 9.8%) and low (0.17 U; 0.3%) phenotypes. The occurrence of the TPMT mutations 238G>C, 460G>A and 719A>G was investigated in all individuals with low or intermediate phenotype, and in 43 with high-activity phenotype. None and two mutant alleles were associated with high-or low-activity phenotypes, respectively, whereas one mutant allele was detected in 26 of the 30 intermediate phenotype individuals. The allele frequencies of TPMT Ã 2, TPMT Ã 3A and TPMT Ã 3C did not differ between individuals classed as Euro-derived (0.76%, 2.03% and 2.54%, respectively) or having interethnic admixture (0.60%, 1.81% and 1.81%, respectively). Furthermore, within each of these groups, the frequencies of TPMT Ã 3A and TPMT Ã 3C were not significantly different. Brazil has one of the most heterogeneous populations in the world. Extensive interethnic crosses over the last 500 years, between autochthonous Amerindians, European colonizers and Africans contributed to the gene pool of the present-day approximately 175 million Brazilians. The heterogeneity of the Brazilian population has important implications for pharmacogenetics because extrapolation of data derived from well-defined ethnic groups is clearly not applicable to the majority of Brazilians. Recognition of this fact has stimulated pharmacogenetic studies in the Brazilian population, and we report the first systematic investigation of genetic polymorphism of thiopurine S-methyltransferase (TPMT; EC 2.1.1.67) in Brazilians. A seminal study on a Caucasian-American population revealed that the TPMT activity displays a trimodal distribution, with 89% of individuals exhibiting high activity, 11% exhibiting intermediate activity and approximately one in 300 having deficient activity [1]. The genetic basis and the molecular mechanisms underlying TPMT polymorphism have been intensively investigated and, to our knowledge, nine nonfunctional mutant alleles have been described to date [2]. Four of these alleles, namely TPMT Ã 2 (238G.C), TPMT Ã 3A (460G.A and 719A.G), TPMT Ã 3B (460G.A) and TPMT Ã 3C (719A.G) account for 78-95% of the lower-activity genotypes in different populations [3,4]. In the present study, phenotyping and genotyping procedures were combined to evaluate the polymorphism of TPMT in 306 healthy Brazilian subjects. Preliminary results have been presented previously in abstract form [5].The study protocol was approved by the Ethics Committee of the Brazilian National Cancer Institute (INCA), and written informed consent was obtained from all volunteers, who were recruited at the INCA blood bank. Previously described polymerase chain reaction-based methods [4] and radiochemical assay [6,7] were emp...

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confidence: 71%

Thiopurine methyltransferase phenotypes and genotypes in Brazilians

2003

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“…Thus, TPMT enzyme activity may provide a better indication of the patient's actual ability to handle thiopurines than genotype. Further complicating the issue is the fact that thiopurine drugs induce TPMT activity, especially in heterozygotes (ϳ30% increase), indicating that baseline TPMT activity may not predict activity during treatment (Chocair et al, 1992;Schutz et al, 1995;Cuffari et al, 2004).…”

Section: Thiopurine Methyltransferasementioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…When individuals with low or undetectable TPMT activity received standard doses of azathioprine, they had high concentrations of the active metabolites 6-thioguanine nucleotides and drug-induced myelosuppression. On the other hand, azathioprine efficacy will be reduced in patients with very high levels of TPMT activity which can be attributed to its rapid metabolization (Chocair et al, 1992;Soria-Royer et al, 1993). TPMT activity correlates with both short-and long-term results after renal transplantation (Thervet et al, 2001).…”

Section: Azathioprinementioning

confidence: 99%

Pharmacogenetics and Renal Transplantation

Cheung¹

2011

Kidney Transplantation - New Perspectives

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The Importance of Thiopurine Methyltransferase Activity for the Use of Azathioprine in Transplant Recipients1

Cited by 163 publications

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Thiopurine methyltransferase phenotypes and genotypes in Brazilians

Thiopurine methyltransferase phenotypes and genotypes in Brazilians

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics and Renal Transplantation

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