Pharmacogenetic studies of thiopurine methyltransferase genotype‐phenotype concordance and effect of methotrexate on thiopurine metabolism

The discovery and implementation of thiopurine methyltransferase (TPMT) pharmacogenetics has been a success story and has reduced the suffering from serious adverse reactions during thiopurine treatment of childhood leukaemia and inflammatory bowel disease. This MiniReview summarizes four studies in...

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Bibliographic Details
Published in:Basic & clinical pharmacology & toxicology 2021-01, Vol.128 (1), p.52-65
Main Authors: Zimdahl Kahlin, Anna, Helander, Sara, Wennerstrand, Patricia, Vikingsson, Svante, Mårtensson, Lars‐Göran, Appell, Malin Lindqvist
Format: Article
Language:English
Subjects:
Children
Enzymatic activity
Enzyme activity
Enzymes
Folic acid
Gene expression
Genotypes
Genotyping
Inflammatory bowel diseases
Intestine
Leukemia
Medical treatment
Metabolism
Methotrexate
Methyltransferase
Minireview
Minireviews
Pharmacogenetics
Pharmacology
Phenotypes
Phenotyping
Thiopurine S-methyltransferase
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Summary:The discovery and implementation of thiopurine methyltransferase (TPMT) pharmacogenetics has been a success story and has reduced the suffering from serious adverse reactions during thiopurine treatment of childhood leukaemia and inflammatory bowel disease. This MiniReview summarizes four studies included in Dr Zimdahl Kahlin's doctoral thesis as well as the current knowledge on this field of research. The genotype‐phenotype concordance of TPMT in a cohort of 12 663 individuals with clinically analysed TPMT status is described. Notwithstanding the high concordance, the benefits of combined genotyping and phenotyping for TPMT status determination are discussed. The results from the large cohort also demonstrate that the factors of gender and age affect TPMT enzyme activity. In addition, characterization of four previously undescribed TPMT alleles (TPMT*41, TPMT*42, TPMT*43 and TPMT*44) shows that a defective TPMT enzyme could be caused by several different mechanisms. Moreover, the folate analogue methotrexate (MTX), used in combination with thiopurines during maintenance therapy of childhood leukaemia, affects the metabolism of thiopurines and interacts with TPMT, not only by binding and inhibiting the enzyme activity but also by regulation of its gene expression.
ISSN:1742-7835
1742-7843
1742-7843
DOI:10.1111/bcpt.13483