Population characteristics of hepatic dihydropyrimidine dehydrogenase activity, a key metabolic enzyme in 5-fluorouracil chemotherapy

Dihydropyrimidine dehydrogenase is the initial rate-limiting enzyme in catabolism of 5-fluorouracil, one of the most widely used cancer chemotherapeutic agents. Previous studies have shown the clinical importance of determination of dihydropyrimidine dehydrogenase in patients with cancer, particularly in those with deficiency of this enzyme who experience severe 5-fluorouracil-associated toxicity (including death) after 5-fluorouracil treatment. In the present study, dihydropyrimidine dehydrogenase activity was determined in 138 donor liver samples. A normal distribution of human liver dihydropyrimidine dehydrogenase activity was shown. The mean enzyme activity was compared across different groups by age, gender, and race, with no significant differences observed except that the mean enzyme activity in women was slightly higher than that observed in men. With use of a polyclonal antibody generated against human liver dihydropyrimidine dehydrogenase, Western blot analysis showed that dihydropyrimidine dehydrogenase protein in the liver cytosol correlated with the activity of this enzyme.