Zebularine Metabolism by Aldehyde Oxidase in Hepatic Cytosol From Humans, Monkeys, Dogs, Rats, and Mice: Influence of Sex and Inhibitors

Bioorg Med Chem. 2006 Jan 1;14(1):62-6. doi: 10.1016/j.bmc.2005.07.053. Epub 2005 Sep 6.

Abstract

To aid in the clinical evaluation of zebularine, a potential oral antitumor agent, we initiated studies on the metabolism of zebularine in liver cytosol from humans and other mammals. Metabolism by aldehyde oxidase (AO, EC 1.2.3.1) was the major catabolic route, yielding uridine as the primary metabolite, which was metabolized further to uracil by uridine phosphorylase. The inhibition of zebularine metabolism was studied using raloxifene, a known potent inhibitor of AO, and 5-benzylacyclouridine (BAU), a previously undescribed inhibitor of AO. The Michaelis-Menten kinetics of aldehyde oxidase and its inhibition by raloxifene and BAU were highly variable between species.

MeSH terms

  • Aldehyde Oxidase / antagonists & inhibitors
  • Aldehyde Oxidase / metabolism*
  • Animals
  • Chromatography, High Pressure Liquid
  • Cytidine / analogs & derivatives*
  • Cytidine / metabolism
  • Cytosol / enzymology
  • Cytosol / metabolism*
  • Dogs
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Haplorhini
  • Humans
  • Liver / enzymology
  • Liver / metabolism*
  • Macaca fascicularis
  • Male
  • Mice
  • Rats

Substances

  • Enzyme Inhibitors
  • Cytidine
  • pyrimidin-2-one beta-ribofuranoside
  • Aldehyde Oxidase