Isolation of a human thiopurine S-methyltransferase (TPMT) complementary DNA with a single nucleotide transition A719G (TPMT*3C) and its association with loss of TPMT protein and catalytic activity in humans*

Loennechen, Thrina; Yates, Charles R.; Fessing, Michael Y.; Relling, Mary V.; Krynetski, Eugene Y.; Evans, William E.

doi:10.1016/s0009-9236(98)90021-2

Cited by 72 publications

(40 citation statements)

References 12 publications

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“…Second explanation maybe the relatively low dose of AZAadministration in Japan (commonly 1 mg/kg/day), compared to the dose commonlyprescribed for the treatment of rheumatoid arthritis in Caucasians (2-3 mg/kg/day). However, recently it was reported that erythrocytes obtained from patients with TPMT*3AfTPMT*3C genotype showed no TPMT function and patients with TPMT*1/TPMT*3C showed intermediate TPMTactivity, indicating that TPMT*3Callele is nonfunctional in vivo (6), and when expressed in humans, TPMT*3Cis likely associated with lower TPMTprotein levels and catalytic activity in erythrocytes (13). Considering these, the second explanation, that the relatively low dose of AZA administration in Japan is the reason for the mildness of side effects, is considered to be more plausible.…”

Section: Discussionmentioning

confidence: 99%

Thiopurine Methyltransferase Genotype and the Toxicity of Azathioprine in Japanese.

et al. 1999

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Objective Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that preferentially catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including Azathioprine (AZA). It has been reported that the level ofAZA toxicity is dependent on the TPMT genotypes in Caucasian individuals; we thus investigated this relationship in Japanese. Methods The TPMTgenotype was determined using peripheral blood cell DNAobtained from 36 Japanese patients with rheumatic diseases who were treated with AZA,by polymerase chain reaction (PCR) technique. Duration ofAZAadministration, white blood cell counts before and after AZAadministration, and side effects were investigated in each subject, and were compared between the patients with or without TPMTmutation. Results The TPMTallelotype was TPMT*1ITPMT*1 in 33 (91.7%) and TPMT*1/TPMT*3Cin 3 (8.3%) individuals.All 3 patients (100%) with the mutant TPMTallele (TPMT*3C) discontinued AZAtreatment due to leucopenia while only 4 patients (12%) without mutant TPMTalleles showed leucopenia (p=0.0049, Fisher's exact test). However, leucopenia developed relatively late in patients with mutant TPMT. Conclusion The TPMTmutant allele, TPMT*3C,also exists in Japanese individuals, and the bone marrow toxicity of AZAis likely stronger in patients with this mutant allele. (Internal Medicine 38: 944-947, 1999)

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Section: Discussionmentioning

confidence: 99%

Thiopurine Methyltransferase Genotype and the Toxicity of Azathioprine in Japanese.

et al. 1999

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“…Thus, the homozygous deficiency in humans is characterized by almost undetectable levels of TPMT protein; heterozygotes have intermediate protein and activity levels; and homozygous wild-type individuals have high levels of protein and activity (28,29).…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics

et al. 2007

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The recessive deficiency in thiopurine methyltransferase (TPMT), caused by germ-line polymorphisms in TPMT, can cause severe toxicity after mercaptopurine. However, the significance of heterozygosity and the effect of the polymorphism on thioguanine or in the absence of thiopurines is not known. To address these issues, we created a murine knockout of Tpmt. Pharmacokinetic and pharmacodynamic studies of mercaptopurine and thioguanine were done in Tpmt Tpmt+/À , and Tpmt +/+ mice and variables were compared among genotypes. Methylated thiopurine and thioguanine nucleotide metabolites differed among genotypes after treatment with mercaptopurine (P < 0.0001 and P = 0.044, respectively) and thioguanine (P = 0.011 and P = 0.002, respectively). Differences in toxicity among genotypes were more pronounced following treatment with 10 daily doses of mercaptopurine at 100 mg/kg/d (0%, 68%, and 100% 50-day survival; P = 0.0003) than with thioguanine at 5 mg/ kg/d (0%, 33%, and 50% 15-day survival; P = 0.07) in the Tpmt À/À , Tpmt +/À , and Tpmt +/+ genotypes, respectively. Myelosuppression and weight loss exhibited a haploinsufficient phenotype after mercaptopurine, whereas haploinsufficiency was less prominent with thioguanine. In the absence of drug challenge, there was no apparent phenotype. The murine model recapitulates many clinical features of the human polymorphism; indicates that mercaptopurine is more affected by the TPMT polymorphism than thioguanine; and provides a preclinical system for establishing safer regimens of genetically influenced antileukemic drug therapy. [Cancer Res 2007;67(10):4965-72]

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“…For example, mean erythrocyte TPMT activity in African subjects was 20% percent lower that in Caucasians from the same location [4]. Based on the population phenotype-genotype studies performed to date, assays for the molecular diagnosis of TPMT deficiency have focused on TPMT * 2 (G238C) [8], TPMT * 3A (G460A/A719G) [9], and TPMT * 3C (A719G) [10]. These three mutant alleles account for the majority of low activity alleles in human populations studied to date [11].…”

Section: Introductionmentioning

confidence: 99%

Phenotyping and genotyping study of thiopurine S‐methyltransferase in healthy Chinese children: A comparison of Han and Yao ethnic groups

Zhang¹,

Guan²,

et al. 2004

Brit J Clinical Pharma

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AimsEthnicity is an important variable influencing drug response. Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs. Previous population studies have identified ethnic variations in both phenotype and genotype of TPMT , but limited information is available within Chinese population that comprises at least 56 ethnic groups . The current study was conducted to compare both phenotype and genotype of TPMT in healthy Han and Yao Chinese children. MethodsTPMT activity was measured in healthy Chinese children by a H PLC assay ( n = 213, 87 Han Chinese and 126 Yao Chinese). Allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) were used to determine the frequency of TPMT mutant alleles ( TPMT * 2 , TPMT * 3 A, TPMT * 3B and TPMT * 3C ) in these children. ResultsThere was no significant difference in the mean TPMT activity between Han and Yao Chinese children. A unimodal distribution of TPMT activity in Chinese children was found and the mean TPMT activity was 13.32 ± 3.49 U ml -1 RBC. TPMT activity was not found to differ with gender, but tended to increase with age in Yao Chinese children. TPMT * 2, TPMT * 3B and TPMT * 3A were not detected, and only one TPMT * 3C heterozygote (Han child) was identified in 213 Chinese children. Erythrocyte TPMT activity of this TPMT * 3C heterozygote was 12.36 U ml -1 RBC. The frequency of the known mutant TPMT alleles was 0.2% [1/426] in Chinese children. ConclusionThe frequency distribution of RBC TPMT activity was unimodal. The frequency of the known mutant TPMT alleles in Chinese Children is low and TPMT * 3C appears to be the most prevalent among the tested mutant TPMT alleles in this population.J.-P. Zhang et al. 16458 :2 Br J Clin Pharmacol

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Isolation of a human thiopurine S-methyltransferase (TPMT) complementary DNA with a single nucleotide transition A719G (TPMT3C) and its association with loss of TPMT protein and catalytic activity in humans

Abstract: These data establish that the TPMT*3C allele is expressed in humans and is associated with lower immunodetectable TPMT protein and catalytic activity.

Cited by 72 publications

References 12 publications

Thiopurine Methyltransferase Genotype and the Toxicity of Azathioprine in Japanese.

Thiopurine Methyltransferase Genotype and the Toxicity of Azathioprine in Japanese.

Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics

Phenotyping and genotyping study of thiopurine S‐methyltransferase in healthy Chinese children: A comparison of Han and Yao ethnic groups

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