Dihydropyrimidine Dehydrogenase

Dihydropyrimidine dehydrogenase (DPD) catalyzes the initial rate-limiting step in the catabolism of endogenous pyrim-idines and 5-FU. It is encoded on chromosome 1. DPD activity is inherited as an autosomal codominant trait. Approximately 0.1% of the population carry homozygous inactivating mutations whereas 3% are heterozygotes. DPD activity has a normal distribution in the population and there is manifold interindividual variability, although not obviously age- or gender-related. The most common mutant allele, DPYD*2A, results from a G to A transition that leads to deletion of exon 14 and thus ending with a truncated protein, which is subsequently degraded by the ubiquitin-proteasome system.

Individuals with deficient DPD activity experience profound systemic toxicity (myelosuppression, diarrhea, neuro-toxicity) upon exposure to 5-FU, which may potentially result in fatalities. Assessment of DPD activity in human peripheral blood mononuclear cells correlates well with total body enzyme activity. On the other hand, high level of DPD mRNA expression in colorectal tumors confers resistance to 5-FU.109

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