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An enzymatic study was performed to clarify the mechanism of 18 acute deaths in patients who had received the new oral antiviral drug, sorivudine (SRV), during anticancer chemotherapy with 5-fluorouracil (5-FU) prodrugs. Human dihydropyrimidine dehydrogenase (hDPD), playing a key role in the liver as the rate-limiting enzyme in catabolism of 5-FU, was expressed in E. coli, purified, and incubated in the presence of NADPH with SRV or (E)-5-(2-bromovinyl)uracil (BVU), a metabolite of SRV. hDPD was rapidly and irreversibly inactivated by BVU, but not by SRV. Radioactivity of [14C]BVU was incorporated into hDPD in the presence of NADPH in a manner reciprocal to the enzyme inactivation. In the absence of NADPH, hDPD was not inactivated by BVU, nor radiolabeled with [14C]BVU. Thus, as we demonstrated previously with studies using the rat, the acute deaths were strongly suggested to be attributable to markedly elevated tissue 5-FU levels, which were responsible for irreversible inhibition of hDPD by covalent binding of a reduced form of BVU as a suicide inactivator. A significant linear correlation (r=0.58, p=0.005) was observed between liver-DPD activity and levels of the immuno-detectable protein with anti-hDPD-anti-serum, indicating that the antibody could be a valuable tool for the DPD deficiency screening.

INACTIVATION MECHANISM OF HUMAN DIHYDROPYRIMIDINE DEHY DROGENASE BY 5-(2'-BROMOVINYL)URACIL, A METABOLITE OF THE ANTIVIRAL, SORIVUDINE