Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver.
Recently, we have reported that tegafur, an anticancer agent, is biotransformed into active drug 5-fluorouracil (5-FU) by cytochromes P450 1A2, 2A6, and 2C8 in human liver microsomes (T. Komatsu et al., Drug Metab. Dispos, 28: 1457-1463, 2000). Because the conversion of tegafur into 5-FU has also been reported to be catalyzed by cytosolic thymidine phosphorylase (dThdPase), the involvement of human liver microsomes and cytosol and individual differences in 5-FU formation from tegafur were investigated. In 14 human samples, the mean rates of 5-FU formation in liver microsomes were 5-fold and 2-fold higher than those in liver cytosol at substrate concentrations of 100 microM and 1 mM tegafur, respectively. In the presence of 5-chloro-2,4-dihydroxypyridine, a dihydropyrimidine dehydrogenase inhibitor, the rates of 5-FU formation by the combination of liver microsomes and cytosol showed 5- and 3-fold interindividual differences at 100 microM and 1 mM tegafur, respectively. Kinetic analysis of human liver cytosolic 5-FU formation indicated an apparent higher Km value (16 +/- 4 mM) than that of liver microsomes (1.8 +/- 0.3 mM) with similar Vmax values. Human liver cytosolic 5-FU formation was confirmed to be catalyzed by dThdPase with correlation and chemical inhibition studies. These results suggested that 5-FU formation from tegafur in human liver was mainly catalyzed by microsomal P450 at low concentrations of tegafur, but the contribution of cytosolic 5-FU formation by dThdPase would be important at high concentrations.
Komatsu
T
T
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Yamazaki
H
H
Shimada
N
N
Nagayama
S
S
Kawaguchi
Y
Y
Nakajima
M
M
Yokoi
T
T
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D011725:Pyridines / Q000494:pharmacology; D005641:Tegafur / Q000493:pharmacokinetics / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000378:metabolism*; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D011725:Pyridines; D005641:Tegafur; D003577:Cytochrome P-450 Enzyme System; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C104201:gimeracil