PT  - JOURNAL ARTICLE
AU  - Harris, James W.
AU  - Rahman, Atiqur
AU  - Kim, Bok-Ryang
AU  - Guengerich, F. Peter
AU  - Collins, Jerry M.
TI  - Metabolism of Taxol by Human Hepatic Microsomes and Liver Slices: Participation of Cytochrome P450 3A4 and an Unknown P450 Enzyme
DP  - 1994 Aug 01
TA  - Cancer Research
PG  - 4026--4035
VI  - 54
IP  - 15
4099  - http://cancerres.aacrjournals.org/content/54/15/4026.short
4100  - http://cancerres.aacrjournals.org/content/54/15/4026.full
SO  - Cancer Res1994 Aug 01; 54
AB  - Incubation of taxol with human hepatic microsomal fractions or freshly isolated human liver slices yields three metabolite high performance liquid chromatography peaks, metabolite A, metabolite B, and 6α-hydroxytaxol. These metabolites are formed in patients given taxol, with 6α-hydroxytaxol formation representing the principal biotransformation pathway. Metabolite B and 6α-hydroxytaxol are shown to be products of different, highly regioselective cytochrome P-450 (P450) enzymes, while metabolite A results from stepwise metabolism by each of these enzymes. Correlation of metabolite B formation with P450 3A markers was good (r2 = 0.91–0.94), but the correlation of 6α-hydroxytaxol formation with markers for several P450 enzymes was poor. Chemical inhibitors that selectively inhibited metabolite B formation (troleandomycin, cyclosporine), that selectively inhibited 6α-hydroxytaxol formation (naringenin, quercetin), or that nonselectively inhibited both pathways (felodipine, ketoconazole) were found. Metabolite B formation was selectively reduced by anti-P450 3A4 antibodies. Expressed human P450 3A4 preparations were efficient catalysts of metabolite B formation; no expressed P450 preparation tested showed a capacity for catalyzing taxane 6α-hydroxylation reactions. The combined results of several experimental approaches show that P450 3A4 is the major catalyst of metabolite B formation and that the identity of the P450 enzyme or enzymes responsible for 6α-hydroxytaxol formation cannot be assigned with certainty. ©1994 American Association for Cancer Research.