This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Komatsu, T. Articles by Yokoi, T. Search for Related Content PubMed PubMed Citation Articles by Komatsu, T. Articles by Yokoi, T.

Involvement of Microsomal Cytochrome P450 and Cytosolic Thymidine Phosphorylase in 5-Fluorouracil Formation from Tegafur in Human Liver¹

Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920-0934, Japan [T. K., H. Y., M. N., T. Y.]; Daiichi Pure Chemicals, Ibaraki 312-1182, Japan [N. S.]; and Taiho Pharmaceutical Co., Tokushima 771-0194, Japan [S. N., Y. K.]

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 µM 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 µM and 1 mM tegafur, respectively. Kinetic analysis of human liver cytosolic 5-FU formation indicated an apparent higher K_m value (16 ± 4 mM) than that of liver microsomes (1.8 ± 0.3 mM) 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.

This article has been cited by other articles:

				T. Fukami, M. Nakajima, E. Higashi, H. Yamanaka, H. Sakai, H. L. McLeod, and T. Yokoi CHARACTERIZATION OF NOVEL CYP2A6 POLYMORPHIC ALLELES (CYP2A6*18 AND CYP2A6*19) THAT AFFECT ENZYMATIC ACTIVITY Drug Metab. Dispos., August 1, 2005; 33(8): 1202 - 1210. [Abstract] [Full Text] [PDF]

				M. Rooseboom, J. N. M. Commandeur, and N. P. E. Vermeulen Enzyme-Catalyzed Activation of Anticancer Prodrugs Pharmacol. Rev., March 1, 2004; 56(1): 53 - 102. [Abstract] [Full Text] [PDF]

				F. Mayer, J. T. Hartmann, J. von Pawel, J. Beck, M. Schroeder, I. Boehlke, L. Kanz, and C. Bokemeyer A phase I study of oral uracil-ftorafur plus folinic acid in combination with weekly paclitaxel in patients with solid tumors Ann. Onc., May 1, 2002; 13(5): 755 - 759. [Abstract] [Full Text] [PDF]

				G. J. Peters, C. J. van Groeningen, G. Giaccone, and R. M. White Jr Fluorouracil (5FU) Pharmacokinetics in 5FU Prodrug Formulations With a Dihydropyrimidine Dehydrogenase Inhibitor J. Clin. Oncol., November 15, 2001; 19(22): 4267 - 4269. [Full Text]