Dihydropyrimidine dehydrogenase pharmacogenetics in Caucasian subjects.
OBJECTIVE
Dihydropyrimidine dehydrogenase (DPD) catalyses the reduction of pyrimidines, including the anticancer agent 5-fluorouracil (5FU). Impaired 5FU degradation, through low DPD activity, has led to severe, life-threatening or fatal toxicity after administration of 5FU. Complete DPD deficiency is associated with the inherited metabolic disease thymine uraciluria. Several mutations in the gene encoding DPD have recently been identified, but the phenotype-genotype concordance of these alterations in the general population has not been reported.


METHODS
Mononuclear cells were isolated from whole blood and DPD activity was determined after ex vivo incubation with 14C-5FU followed by h.p.1.c. analysis of 5FU metabolites. Analysis of mutations in the DPD gene at an exon splice site, codons 534, 543, and 732, and a deletion at base 1897 (deltaC1897) were performed in 30 subjects with the lowest and 30 subjects with the highest enzyme activity using PCR-RFLP.


RESULTS
DPD activity was measured in 226 Caucasian subjects and was highly variable (range 19.1-401.4 pmol min(-1)mg(-1) protein). Mutations were frequently observed at codons 543 (allele frequency 28%), 732 (allele frequency 5.8%), and 534 (allele frequency 0.8%), but were not associated with low DPD activity. There were no splice site or deltaC1897 mutations found in this population.


CONCLUSIONS
The five mutations analysed in this study are insufficient for identification of patients at risk for 5FU toxicity or thymine uraciluria. Both the splice site mutation and deltaC1897 are relatively rare in the general Caucasian population. Therefore, identification of further molecular alterations is required to facilitate the use of DPD analysis in genetic diagnosis and cancer therapeutics.
Ridge
S A
SA
Department of Medicine & Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, United Kingdom.
Sludden
J
J
Brown
O
O
Robertson
L
L
Wei
X
X
Sapone
A
A
Fernandez-Salguero
P M
PM
Gonzalez
F J
FJ
Vreken
P
P
van Kuilenburg
A B
AB
van Gennip
A H
AH
McLeod
H L
HL
D000483:Alleles; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008297:Male; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D012606:Scotland; D012907:Smoking; D044465:White People / Q000235:genetics*
D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)