title: Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme.
abstract: 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 6 alpha-hydroxytaxol. These metabolites are formed in patients given taxol, with 6 alpha-hydroxytaxol formation representing the principal biotransformation pathway. Metabolite B and 6 alpha-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 6 alpha-hydroxytaxol formation with markers for several P450 enzymes was poor. Chemical inhibitors that selectively inhibited metabolite B formation (troleandomycin, cyclosporine), that selectively inhibited 6 alpha-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 6 alpha-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 6 alpha-hydroxytaxol formation cannot be assigned with certainty.
authors.affiliation: Division of Clinical Pharmacology, United States Food and Drug Administration, Rockville, Maryland 20857.
authors.forename: J W
authors.initials: JW
authors.lastname: Harris
authors.forename: A
authors.initials: A
authors.lastname: Rahman
authors.forename: B R
authors.initials: BR
authors.lastname: Kim
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
authors.forename: J M
authors.initials: JM
authors.lastname: Collins
mesh_terms: D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043823:Taxoids; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D043823:Taxoids; C086219:6-hydroxytaxol; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel