PT  - JOURNAL ARTICLE
AU  - Tomoko Komatsu
AU  - Hiroshi Yamazaki
AU  - Noriaki Shimada
AU  - Miki Nakajima
AU  - Tsuyoshi Yokoi
TI  - Roles of Cytochromes P450 1A2, 2A6, and 2C8 in 5-Fluorouracil Formation from Tegafur, an Anticancer Prodrug, in Human Liver Microsomes
DP  - 2000 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1457--1463
VI  - 28
IP  - 12
4099  - http://dmd.aspetjournals.org/content/28/12/1457.short
4100  - http://dmd.aspetjournals.org/content/28/12/1457.full
SO  - Drug Metab Dispos2000 Dec 01; 28
AB  - 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 μM. Kinetic analysis revealed that CYP1A2 had the highestVmax/Km value and that the Vmax value of CYP2A6 was high in 5-FU formation. In human liver microsomes, the activities of 5-FU formation from 10 μM, 100 μM, and 1 mM tegafur were significantly correlated with both coumarin 7-hydroxylation (r = 0.83, 0.86, and 0.74) and paclitaxel 6α-hydroxylation (r = 0.77, 0.62, and 0.85) activities, respectively. Coumarin efficiently inhibited the 5-FU formation activities from 100 μM 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. The American Society for Pharmacology and Experimental Therapeutics