Phenotypic and clinical implications of variants in the dihydropyrimidine dehydrogenase gene

Biochimica Et Biophysica Acta
André B P van KuilenburgCarlo R Largiadèr

Abstract

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil, thymine and the antineoplastic agent 5-fluorouracil. Genetic variations in the gene encoding DPD (DPYD) have emerged as predictive risk alleles for 5FU-associated toxicity. Here we report an in-depth analysis of genetic variants in DPYD and their consequences for DPD activity and pyrimidine metabolites in 100 Dutch healthy volunteers. 34 SNPs were detected in DPYD and 15 SNPs were associated with altered plasma concentrations of pyrimidine metabolites. DPD activity was significantly associated with the plasma concentrations of uracil, the presence of a specific DPYD mutation (c.1905+1G>A) and the combined presence of three risk variants in DPYD (c.1905+1G>A, c.1129-5923C>G, c.2846A>T), but not with an altered uracil/dihydrouracil (U/UH2) ratio. Various haplotypes were associated with different DPD activities (haplotype D3, a decreased DPD activity; haplotype F2, an increased DPD activity). Functional analysis of eight recombinant mutant DPD enzymes showed a reduced DPD activity, ranging from 35% to 84% of the wild-type enzyme. Analysis of a DPD homology model indicated that the structural effect of the...Continue Reading

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Citations

Mar 16, 2017·Anti-cancer Drugs·Andrea BotticelliFederica Mazzuca
Jul 27, 2017·Pharmacogenomics·Xandra García-González, Luis A López-Fernández
May 6, 2019·Pharmaceutics·Theodore J WigleRichard B Kim
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Jun 13, 2020·Cancer Chemotherapy and Pharmacology·Xandra García-GonzálezLuis A López-Fernández
Oct 27, 2020·The Journal of Gene Medicine·Shaik Mohammad NaushadVijay Kumar Kutala
Feb 6, 2021·Cancer Chemotherapy and Pharmacology·Jatta SaarenheimoAndré B P van Kuilenburg
Mar 27, 2021·Frontiers in Genetics·Jorge E B da RochaMichèle Ramsay

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