Characterization of a novel sequence variant, TPMT*28, in the human thiopurine methyltransferase gene

Appell, Malin Lindqvist; Wennerstrand, Patricia; Peterson, Curt; Hertervig, Erik; Mårtensson, Lars-Göran

doi:10.1097/fpc.0b013e3283402ee4

Cited by 28 publications

(33 citation statements)

References 26 publications

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“…Single nucleotide polymorphisms in the TPMT gene (6p22.3) affect the enzyme's rate kinetics, with 29 different alleles described to date. 10,11 Approximately 90% of individuals have normal to high TPMT activity, 10% have intermediate activity, and 1 in 220 to 300 individuals is homozygous for mutant alleles with low to almost undetectable enzymatic activity. 10,12 Utilizing the phenotypic classification when initiating therapy has allowed both individuals with normal and intermediate activity to be treated with fewer instances of hematopoetic toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Approximately 90% of individuals have normal to high TPMT activity, 10% have intermediate activity, and 1 in 220 to 300 individuals is homozygous for mutant alleles with low to almost undetectable enzymatic activity. 10,12 Utilizing the phenotypic classification when initiating therapy has allowed both individuals with normal and intermediate activity to be treated with fewer instances of hematopoetic toxicity. 7,13 It particularly helps identify and precludes administration to patients with significant enzyme deficiency who would be at risk for excessive accumulation of active metabolites.…”

Section: Discussionmentioning

confidence: 99%

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Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring

Caufield

Tom

2013

Journal of the American Academy of Dermatology

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Background Azathioprine is prescribed as a corticosteroid-sparing agent for many inflammatory conditions, including refractory atopic dermatitis (AD). There is limited prospective data on its appropriate use and monitoring for children with AD. Objectives This study was designed to assess clinical response to azathioprine, determine the necessity for repeat measurement of thiopurine methyltransferase (TPMT) activity during treatment, and test the utility of measuring levels of the metabolites 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP). Methods Twelve children with severe, recalcitrant AD were treated with oral azathioprine and followed prospectively. Disease severity was determined by the SCORing Atopic Dermatitis Index. Baseline TPMT activity was measured and this was repeated along with 6-TGN and 6-MMP measurement at times of stable improvement, inadequate response, or change in response. Results Azathioprine therapy was associated with clinical improvement in all but one subject. There were few adverse effects. Three subjects showed a significant change in TPMT activity during treatment: two had a mild decrease and one demonstrated enzyme inducibility with an increase from the intermediate to the normal activity range. These changes, but not 6-TGN or 6-MMP levels, inversely correlated with the clinical response to therapy. Limitations Small sample size Conclusions Azathioprine can be of benefit in the treatment of recalcitrant pediatric AD. Repeat assessment of TPMT activity may be helpful for evaluation of non–response or change in response and warrants further study. In contrast, measurement of thiopurine metabolites during treatment was not clinically useful.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring

Caufield

Tom

2013

Journal of the American Academy of Dermatology

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“…The TPMT enzyme activity in MOLT4 cells was determined by measuring the rate of formation of 6-methyl-mercaptopurine from 6-MP using 14 C-labeled S-adenosyl-Lmethionine as the methyl group donor [12]. An amount of 200 µg of the total cellular protein was incubated in duplicates for 2 hours at 37°C in 400 µl of 47 mmol/l potassium phosphate buffer (pH 7.…”

Section: Tpmt Enzyme Activity In Molt4 Cellsmentioning

confidence: 99%

Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia

Wennerstrand

Mårtensson

Söderhäll

et al. 2013

Eur J Clin Pharmacol

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METHODSFifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before and 66 hours after start of high-dose MTX infusions. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukemic cell line. RESULTSForty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity compared to genotype at the time of diagnosis. TPMT decreased significantly 66 hours after the start of high-dose MTX infusions (-9.2 per cent, p=0.013). MTX bound to recombinant TPMT protein and inhibited the TPMT enzyme to a remaining activity of 16 percent. CONCLUSIONSThis study shows that TPMT genotyping should be preferred in children with ALL, since 40per cent of TPMT wild-type children are at risk of initial under-dosing of 6-MP in cases where 3 only TPMT enzyme activity is determined. MTX inhibits the TPMT enzyme activity after high-dose MTX infusions due to protein binding.

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“…The 611T > C (rs79901429) SNP was identified in a Swedish family with Italian ancestries, and was numbered TPMT*28 in 2010 [36]. At the same time, Landy et al .…”

Section: Introductionmentioning

confidence: 99%

Nomenclature for alleles of the thiopurine methyltransferase gene

Appell

Berg

Duley

et al. 2013

Pharmacogenetics and Genomics

108

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The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors’ articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G > A) from TPMT*24 to TPMT*30 and position 611 (T > C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.

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Characterization of a novel sequence variant, TPMT*28, in the human thiopurine methyltransferase gene

Abstract: We present a detailed in-vivo and in-vitro characterization of a novel TPMT sequence variant (TPMT28) causing decreased TPMT activity. Individuals carrying TPMT28 might have an increased risk for developing severe side effects if treated with conventional doses of thiopurines.

Cited by 28 publications

References 26 publications

Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring

Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring

Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia

Nomenclature for alleles of the thiopurine methyltransferase gene

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Characterization of a novel sequence variant, TPMT*28, in the human thiopurine methyltransferase gene

Abstract: We present a detailed in-vivo and in-vitro characterization of a novel TPMT sequence variant (TPMT*28) causing decreased TPMT activity. Individuals carrying TPMT*28 might have an increased risk for developing severe side effects if treated with conventional doses of thiopurines.

Cited by 28 publications

References 26 publications

Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring

Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring

Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia

Nomenclature for alleles of the thiopurine methyltransferase gene

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Abstract: We present a detailed in-vivo and in-vitro characterization of a novel TPMT sequence variant (TPMT28) causing decreased TPMT activity. Individuals carrying TPMT28 might have an increased risk for developing severe side effects if treated with conventional doses of thiopurines.