Dihydropyrimidine dehydrogenase activity in human blood mononuclear cells.
Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2) catalyzes the rate-limiting reaction in the catabolism of endogenous uracil and thymine and exogenous fluoropyrimidines. DPD activity was studied in human blood mononuclear cell supernatants utilizing a new and sensitive radiochromatographic assay. Total DPD activity showed a linear correlation with supernatant protein concentration. The affinity constants (Km) for NADPH and thymine were approximately 10 and 1 mumol/l, respectively. Maximal activity (Vmax) was observed at 0.25 mmol/l NADPH and 10 mumol/l thymine, respectively. DPD activity in normal individuals was 8.0 +/- (SD) 2.2 nmol/mg protein/h, and ranged from 4.4 to 12.3 nmol/mg/h (n = 25). This activity range was quite similar to values obtained in patients with metastatic solid tumors treated with fluorodeoxyuridine (FUdR; n = 33, p = 0.57). No correlation was found to exist between mononuclear leucocyte DPD activity and the observed toxicity of FUdR in the tested patients. A bimodal distribution of DPD activity was observed in the patients and in normal individuals. The entire study population tested could be divided into two groups with respect to DPD activity; one group with high (greater than 8 nmol/mg/h) activity and another with low (less than 8 nmol/mg/h) activity. The possibility that sex differences may have been responsible for this distribution of DPD activity could not be excluded. The findings of this study are relevant to the pharmacogenetics of fluoropyrimidines in humans.
Tuchman
M
M
Department of Pediatrics, University of Minnesota Health Sciences Center, Minneapolis.
Roemeling
R V
RV
Hrushesky
W A
WA
Sothern
R B
RB
O'Dea
R F
RF
D000328:Adult; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D042943:Dihydrouracil Dehydrogenase (NADP); D005467:Floxuridine / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010088:Oxidoreductases / Q000097:blood*; D012016:Reference Values; D013941:Thymine / Q000378:metabolism; D014461:Ultracentrifugation
D002250:Carbon Radioisotopes; D005467:Floxuridine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013941:Thymine