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

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

Cancer Research 54(15): 4026-4035

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 (r-2 = 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.

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Accession: 009014122

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PMID: 7913410

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