title: Cytosolic and microsomal activation of doxifluridine and tegafur to produce 5-fluorouracil in human liver.
abstract: OBJECTIVE
  The enzymatic formation of 5-fluorouracil (5-FU) from two fluoropyrimidine prodrugs, doxifluridine (5'-DFUR) and tegafur (FT), was compared in vitro in order to determine whether there are differences between the metabolic profiles of the two prodrugs.
  
  
  METHODS
  Conversion of the two fluoropyrimidine prodrugs to 5-FU was measured by high-performance liquid chromatography at a concentration of 500 micro M using the microsomal and cytosolic fractions of 12 human livers. The degree of correlation between the 5-FU-forming activities was determined using various cytochrome P450-dependent reactions.
  
  
  RESULTS
  Liver microsomes catalyzed 5-FU formation from 5'-DFUR at rates of 10.0-160.1 pmol/min per mg protein and correlated well with CYP2A6-dependent coumarin 7-hydroxylase activity. The rates of microsomal 5-FU formation from FT ranged from 44.9 to 808.3 pmol/min per mg protein and also correlated with coumarin 7-hydroxylase activity. The cytosol fractions catalyzed 5-FU formation from 5'-DFUR at rates of 3,164.6 to 6,026.6 pmol/min per mg protein, almost two orders of magnitude higher than the rates of cytosolic 5-FU formation from FT (46.8-219.0 pmol/min per mg protein).
  
  
  CONCLUSIONS
  The cytosolic enzymes in livers appear to be important for 5-FU formation from 5'-DFUR. Both cytosolic and microsomal enzymes were involved almost equally in 5-FU formation from FT. The increased formation of 5-FU from 5'-DFUR might provide an answer to the question of why similar blood 5-FU levels were retained despite blood 5'-DFUR levels lower than blood FT levels.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Kamiyoga, Tokyo, Japan. sozawa@nihs.go.jp
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Hamada
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Masamichi
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohno
mesh_terms: D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D005467:Floxuridine / Q000378:metabolism*; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D005641:Tegafur / Q000378:metabolism*; D013939:Thymidine Phosphorylase / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D005641:Tegafur; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; C022657:steroid hormone 6-beta-hydroxylase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine