Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2-bromovinyl)uracil derived from the antiviral, sorivudine

Cancer Lett. 1998 Jan 9;122(1-2):107-13. doi: 10.1016/s0304-3835(97)00377-7.


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 produced by human gut flora. 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.

MeSH terms

  • Antiviral Agents / metabolism
  • Antiviral Agents / toxicity*
  • Arabinofuranosyluracil / analogs & derivatives*
  • Arabinofuranosyluracil / metabolism
  • Bromouracil / analogs & derivatives*
  • Bromouracil / toxicity
  • Dihydrouracil Dehydrogenase (NADP)
  • Dose-Response Relationship, Drug
  • Humans
  • Oxidoreductases / antagonists & inhibitors*
  • Recombinant Proteins / antagonists & inhibitors


  • Antiviral Agents
  • Recombinant Proteins
  • Arabinofuranosyluracil
  • Bromouracil
  • 5-(2-bromovinyl)uracil
  • sorivudine
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)