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Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism.
Zimdahl Kahlin, Anna; Helander, Sara; Wennerstrand, Patricia; Vikingsson, Svante; Mårtensson, Lars-Göran; Appell, Malin Lindqvist.
Afiliación
  • Zimdahl Kahlin A; Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • Helander S; Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • Wennerstrand P; Division of Chemistry, Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden.
  • Vikingsson S; Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • Mårtensson LG; Division of Chemistry, Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden.
  • Appell ML; Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Basic Clin Pharmacol Toxicol ; 128(1): 52-65, 2021 Jan.
Article en En | MEDLINE | ID: mdl-32865889
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Metotrexato / Variantes Farmacogenómicas / Metiltransferasas Límite: Humans Idioma: En Revista: Basic Clin Pharmacol Toxicol Asunto de la revista: FARMACOLOGIA / TOXICOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Metotrexato / Variantes Farmacogenómicas / Metiltransferasas Límite: Humans Idioma: En Revista: Basic Clin Pharmacol Toxicol Asunto de la revista: FARMACOLOGIA / TOXICOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Reino Unido