Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes

Drug Metab Dispos. 2000 Dec;28(12):1457-63.


Tegafur, an anticancer prodrug, is bioactivated to 5-fluorouracil (5-FU) mainly by cytochrome P450 (P450) enzymes. The conversion from tegafur into 5-FU catalyzed by human liver microsomal P450 enzymes was investigated. In fourteen cDNA-expressed human P450 enzymes having measurable activities, CYP1A2, CYP2A6, CYP2E1, and CYP3A5 were highly active in catalyzing 5-FU formation at a tegafur concentration of 100 microM. Kinetic analysis revealed that CYP1A2 had the highest V(max)/K(m) value and that the V(max) value of CYP2A6 was high in 5-FU formation. In human liver microsomes, the activities of 5-FU formation from 10 microM, 100 microM, and 1 mM tegafur were significantly correlated with both coumarin 7-hydroxylation (r = 0.83, 0.86, and 0.74) and paclitaxel 6 alpha-hydroxylation (r = 0.77, 0.62, and 0.85) activities, respectively. Coumarin efficiently inhibited the 5-FU formation activities from 100 microM and 1 mM tegafur catalyzed by human liver microsomes that had high coumarin 7-hydroxylation activity. On the other hand, furafylline, fluvoxamine, and quercetin, as well as coumarin, showed inhibitory effects in liver microsomes that had high catalytic activities of 5-FU formation. The other P450 inhibitors examined showed weak or no inhibition in human liver microsomes. Polyclonal anti-CYP1A2 antibody, monoclonal anti-CYP2A6, and anti-CYP2C8 antibodies inhibited 5-FU formation activities to different extents in those two microsomal samples. These results suggest that CYP1A2, CYP2A6, and CYP2C8 have important roles in human liver microsomal 5-FU formation and that the involvement of these three P450 forms differs among individual humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / metabolism*
  • Aryl Hydrocarbon Hydroxylases*
  • Baculoviridae / metabolism
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 Enzyme System / metabolism*
  • Fluorouracil / metabolism*
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / metabolism*
  • Prodrugs / metabolism*
  • Recombinant Proteins / metabolism
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / metabolism*
  • Tegafur / metabolism*


  • Antimetabolites, Antineoplastic
  • Prodrugs
  • Recombinant Proteins
  • Tegafur
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A2 protein, human
  • CYP2A6 protein, human
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2C8
  • Steroid 16-alpha-Hydroxylase
  • Fluorouracil