Metabolism of taxol by human hepatic microsomes and liver slices : participation of cytochrome P450 3A4 and an unknown P450 enzyme

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-hydroxytax...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1994-08, Vol.54 (15), p.4026-4035
Main Authors: HARRIS, J. W, RAHMAN, A, BOK-RYANG KIM, GUENGERICH, F. P, COLLINS, J. M
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Biotransformation
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - metabolism
General aspects
Humans
Kinetics
Liver - metabolism
Medical sciences
Microsomes, Liver - metabolism
Mixed Function Oxygenases - metabolism
Paclitaxel - analogs & derivatives
Paclitaxel - antagonists & inhibitors
Paclitaxel - metabolism
Pharmacology. Drug treatments
Taxoids
Troleandomycin - pharmacology
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Summary: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.
ISSN:0008-5472
1538-7445