title: 5-ethynyl-2(1H)-pyrimidinone: aldehyde oxidase-activation to 5-ethynyluracil, a mechanism-based inactivator of dihydropyrimidine dehydrogenase.
abstract: 5-Ethynyluracil is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) in vitro (Porter et al., J Biol Chem 267: 5236-5242, 1992) and in vivo (Spector et al., Biochem Pharmacol, 46: 2243-2248, 1993. 5-Ethynyl-2(1H)-pyrimidinone was rapidly oxidized to 5-ethynyluracil by aldehyde oxidase. The substrate efficiency (kcat/Km) was 60-fold greater than that for N-methylnicotinamide. In contrast, xanthine oxidase oxidized 5-ethynyl-2(1H)-pyrimidinone to 5-ethynyluracil with a substrate efficiency that was only 0.02% that of xanthine. Because 5-ethynyl-2(1H)-pyrimidinone did not itself inactivate purified DPD in vitro and aldehyde oxidase is predominately found in liver, we hypothesized that 5-ethynyl-2(1H)-pyrimidinone could be a liver-specific inactivator of DPD. We found that 5-ethynyl-2(1H)-pyrimidinone administered orally to rats at 2 micrograms/kg inactivated DPD in all tissues studied. Although 5-ethynyl-2(1H)-pyrimidinone produced slightly less inactivation than 5-ethynyluracil, the two compounds showed fairly similar patterns of inactivation of DPD in these tissues. At doses of 20 micrograms/kg, however, 5-ethynyl-2-pyrimidinone and 5-ethynyluracil produced equivalent inactivation of DPD. Thus, 5-ethynyl-2(1H)-pyrimidinone appeared to be an efficient, but not highly liver-selective prodrug of 5-ethynyluracil.
authors.affiliation: Division of Experimental Therapy, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
authors.forename: D J
authors.initials: DJ
authors.lastname: Porter
authors.forename: J A
authors.initials: JA
authors.lastname: Harrington
authors.forename: M R
authors.initials: MR
authors.lastname: Almond
authors.forename: G T
authors.initials: GT
authors.lastname: Lowen
authors.forename: T P
authors.initials: TP
authors.lastname: Zimmerman
authors.forename: T
authors.initials: T
authors.lastname: Spector
mesh_terms: D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D042943:Dihydrouracil Dehydrogenase (NADP); D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: C086824:5-ethynyl-2(1H)-pyrimidinone; D011355:Prodrugs; D011744:Pyrimidinones; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D014969:Xanthine Oxidase; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D042943:Dihydrouracil Dehydrogenase (NADP)