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...

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Published in:	Clinical cancer research 2001-03, Vol.7 (3), p.675
Main Authors:	Komatsu, T, Yamazaki, H, Shimada, N, Nagayama, S, Kawaguchi, Y, Nakajima, M, Yokoi, T
Format:	Article
Language:	eng
Subjects:	Antimetabolites, Antineoplastic - metabolism Antimetabolites, Antineoplastic - pharmacology Biotransformation Chromatography, High Pressure Liquid Cytochrome P-450 Enzyme System - metabolism Cytosol - enzymology Cytosol - metabolism Dose-Response Relationship, Drug Fluorouracil - metabolism Fluorouracil - pharmacology Humans Kinetics Liver - metabolism Microsomes, Liver - enzymology Pyridines - pharmacology Tegafur - pharmacokinetics Tegafur - pharmacology Thymidine Phosphorylase - metabolism Time Factors
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Summary:	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 μ m and 1 m m 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 μ m and 1 m m tegafur, respectively. Kinetic analysis of human liver cytosolic 5-FU formation indicated an apparent higher K m value (16 ± 4 m m ) than that of liver microsomes (1.8 ± 0.3 m m ) with similar V max 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.
ISSN:	1078-0432 1557-3265