Dihydropyrimidine dehydrogenase (NADP+)

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Dihydropyrimidine dehydrogenase (NADP+) (DPD) is an enzyme that plays a crucial role in the metabolism of pyrimidines, which are essential components of nucleic acids. DPD catalyzes the initial and rate-limiting step in the catabolism of the pyrimidine bases uracil and thymine to beta-alanine and beta-aminoisobutyric acid, respectively. This enzyme is encoded by the DPYD gene in humans.

Function

DPD is involved in the breakdown of pyrimidine bases, which is important for the maintenance of the nucleotide pool balance within the cell. By converting uracil and thymine to more easily excreted products, DPD prevents the potentially toxic accumulation of these bases. The enzyme's activity is critical for the DNA and RNA synthesis processes, as it ensures that the cell has a balanced supply of nucleotides for these essential functions.

Clinical Significance

The activity of DPD is of particular interest in the field of oncology, as it is responsible for the degradation of certain chemotherapy drugs, such as 5-fluorouracil (5-FU) and capecitabine, which are used in the treatment of various cancers. Patients with a deficiency in DPD activity are at a higher risk of developing severe, potentially life-threatening toxicity from these treatments because their bodies cannot effectively break down these drugs. Testing for DPD deficiency is becoming an important part of personalized medicine, allowing for the adjustment of chemotherapy dosages to safer levels for individuals with reduced enzyme activity.

Genetic Variability

Variations in the DPYD gene can lead to reduced or absent activity of the DPD enzyme. These genetic polymorphisms can significantly affect an individual's response to pyrimidine-based chemotherapy agents. Several specific mutations in the DPYD gene have been identified that correlate with decreased enzyme activity. Pharmacogenetic testing for these mutations can help identify patients at risk for severe toxicity from pyrimidine-based chemotherapeutic agents.

Treatment and Management

For patients with DPD deficiency, dose adjustments of certain chemotherapeutic agents are necessary to avoid toxicity. In some cases, alternative treatments that do not rely on DPD for metabolism may be considered. Ongoing research aims to develop more effective strategies for managing patients with DPD deficiency, including the use of enzyme inhibitors or supplemental therapies that can mitigate the risk of toxicity.

See Also

• Pyrimidine metabolism
• Chemotherapy
• Pharmacogenomics
• Nucleotide