Dihydropyrimidine Dehydrogenase (DPD Enzyme Deficiency)
DPD is the rate limiting enzyme involved in the catabolism of pyrimidines
like thymidine and uracil.
DPD is also the main enzyme involved in the degradation of structurally
related compounds like 5-Fluorouracil (5-FU), a widely used anticancer
drug.
Decrease in DPD activity results in toxicity to 5-FU in cancer patients.
A guanine to adenine point mutation in the 5'-splice site consensus
sequence was noted in subjects with DPD deficiency.
On the basis of catalytic activity, and on the basis of the mutation
frequency. a 3% frequency for heterozygotes (-/+) to DPD was predicted,
projecting a 1:1000 homozygotes (+/+) for this mutation across racial lines.
Even heterozygosity for this mutation can result in a large decrease in DPD
activity and an increase in toxicity to 5-FU.
It is recommended that screening for this mutation should be accompanied
by direct measurement of DPD activity prior to 5-FU treatment in cancer
patients. Although this particular mutation is much more frequent than
other mutations in the DPD gene, absence of this splice site mutation does
not rule out the possibility of a decrease in DPD activity due to another
mutation.
References:
Gonzalez FJ, Fernandez-Salguero P. (1995) Diagnostic analysis, clinical
importance and molecular basis of dihydropyrimidine dehydrogenase
deficiency. Trends Pharmacol. Sci. 16:325-327.
van Kuilenburg AB, Vreken P, Beex LV, De Abreu RA, van Gennip AH.
(1998) Severe 5-fluorouracil toxicity caused by reduced dihydropyrimidine
dehydrogenase activity due to heterozygosity for a G-->A point mutation. J.
Inherit. Metab. Dis. 21:280-4.
Wei, X., McLeod, HL., et al.(1996) Molecular basis of the human
dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J.
Clin. Invest. 98:610-615, 1996
McMurrough, J. and McLeod, H.L. (1996) Analysis of the dihydropyrimidine
dehydrogenase polymorphism in a British population. Brit. J. Clin.
Pharmacol. 41:425-427.
For more information go to National Center for Biotechnology Information (NCBI).
Most abstracts and many full length articles can be printed from this web site.
A very good source of information on dpd enzyme and how to obtain information on
Screening Patients for DPD Enzyme Deficiency is available at the following web
site:
http://www.dpdenzyme.com/
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