Abstract
Two siblings were found to have elevated plasma concentrations and increased urinary excretion of uracil (U) and thymine (T) (as high as 50 times normal for U and 100 times normal for T, when compared to 17 healthy adult controls). The female sibling developed severe neurotoxicity after chemotherapy with 5-fluorouracil (5-FU) for breast cancer. Both had normal serum and urinary uric acid concentrations and also normal urinary orotic acid levels. Thymidine kinase activity in the female's WBC was normal 17.30 pmoles/mg protein/min (controls 19.37±7.02). Three other members of the family (mother and two other siblings) had normal plasma and urine levels of U and T. This metabolic aberration can be explained by the decreased degradation of U, T and 5-FU in the liver. Degradation of pyrimidine bases could not be demonstrated in normal fibroblasts. The activity of dihydropyrimidine dehydrogenase was assayed in rat liver. 5-FU was found to be a substrate for this enzyme in vitro. We postulate that the two siblings have a defect in hepatic dihydropyrimidine dehydrogenase causing decreased degradation and enhancement of 5-FU toxicity in one sibling.
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