DPYD

DPYD is the gene that encodes dihydropyrimidine dehydrogenase, an NAD+-dependent enzyme that catalyzes the rate-limiting step in the catabolism of pyrimidines uracil and thymine, and plays a critical role in breaking down the chemotherapy drug 5-fluorouracil (5-FU). The enzyme is primarily expressed in the liver and gut and helps regulate systemic exposure to 5-FU after administration. Deficiency or reduced activity of DPYD can lead to markedly increased 5-FU levels, raising the risk of severe or potentially life-threatening toxicities such as myelosuppression, mucositis, diarrhea, neurotoxicity, and organ injury.

Genetic variation in DPYD influences enzyme activity. Several variants are associated with decreased function, including DPYD2A (c.1905+1G>A, also described as IVS14+1G>A), DPYD13 (c.1679T>G, p.I560S), and c.2846A>T (p.D949V). A haplotype known as HapB3 and other rare variants have also been linked to reduced activity. Carriers may not uniformly develop toxicity, and risk depends on the combination of variants (zygosity) and other factors. Because of this, pre-treatment testing for DPYD variants is recommended in many guidelines to guide 5-FU dosing.

Clinical implications include dose modification or alternative therapies for individuals with reduced DPYD activity. CPIC and other pharmacogenetic guidelines provide variant-specific dosing recommendations to minimize toxicity while maintaining efficacy. Testing can be genotypic (screening for known variants) or sequencing-based, and may be complemented by phenotypic assessments of DPYD activity, such as measuring enzyme activity or metabolite ratios. DPYD testing is part of precision oncology efforts to personalize fluoropyrimidine therapy.