Abstract
In 1993, there were 18 acute deaths in Japanese patients who had the viral disease, herpes zoster, and were administered with a new anti-viral drug, sorivudine (SRV, 1-β-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil). All the dead patients were receiving a 5-fluorouracil (5-FU) prodrug for anti-cancer chemotherapy when they were administered with SRV. Studies on toxicokinetics in rats and on their hepatic dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme for the 5-FU catabolism in the rat and human, strongly suggested that in the patients who received both SRV and 5-FU prodrug, tissue levels of highly toxic 5-FU increased extremely as a result of irreversible inactivation of DPD in the presence of NADPH by 5-(2-bromovinyl)uracil (BVU), a metabolite formed from SRV by gut flora in rats and humans. Recombinant human (h) DPD was also irreversibly inactivated by [14C]BVU in the presence of NADPH. MALDI-TOF MS analysis of radioactive tryptic fragments from the radiolabeled and inactivated hDPD demonstrated that a Cys residue located at position 671 in the pyrimidine-binding domain of hDPD was modified with an allyl bromide type of reactive metabolite, dihydro-BVU.
