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[Cancer Research 54, 386-392, January 15, 1994]
© 1994 American Association for Cancer Research
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Taxol Metabolism by Human Liver Microsomes: Identification of Cytochrome P450 Isozymes Involved in Its Biotransformation1

Thierry Cresteil2, Bernard Monsarrat, Paul Alvinerie, Jean Marc Tréluyer, Isabel Vieira and Michel Wright

INSERM U75, Université René Descartes, 75730 Paris Cedex 15, France [T. C., J. M. T., I. V], and Centre National de la Recherche Scientifique, Laboratoire de Pharmacologie et de Toxicologie Fondamentales, 31400 Toulouse, France [B. M., P. A., M. W.]

2 To whom requests for reprints should be addressed, at INSERM U75, Université René Descartes, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.

The biotransformation of taxol by human liver was investigated in vitro with microsomes isolated from adult and developing human tissues. In vitro, no metabolism was detected with kidney microsomes, whereas two metabolites were generated by liver microsomes. The most prominent metabolite, termed M5, corresponded to an hydroxylation at the C6 position on the taxane ring, while the other metabolite, termed M4, corresponded to an hydroxylation at the para-position on the phenyl ring at the C3'-position of the C13 side chain. These two taxol derivatives have been shown to be the major metabolites recovered in bile from a patient infused with taxol. Several approaches have been used to identify the cytochrome P450 (CYP) isozymes involved in these reactions. No positive correlation was observed between the in vitro synthesis of these two metabolites, suggesting that two cytochrome P450 isozymes could be involved, al-though they could not be distinguished by their apparent affinities (Km {approx} 15 µM). The formation of metabolite M4 was substantially reduced both by antibody directed against CYP3A and by the addition of CYP3A substrates such as orphenadrine, erythromycin, troleandomycin, and testosterone. Conversely, the formation of metabolite M5 remained unaffected by antibodies against CYP3A and by CYP3A substrates but was sensitive to diazepam inhibition, a preferential substrate of CYP2C. Correlation between CYP2C content or diazepam demethylation and the synthesis of metabolite M5 was highly positive. The formation of metabolite M4 developed during the early postnatal period. In contrast, the synthesis of metabolite M5 rose only after 3 months of age. These data clearly implicate CYP3A in the formation of metabolite M4 and CYP2C in the synthesis of metabolite M5. Microsomes from patients treated with barbiturates and benzodiazepines increased the formation of metabolite M4 to the level of metabolite M5, demonstrating that drug interactions could modify the human metabolism of taxol.

1 This work was supported by Assistance Publique (DRC 912001), l'Association pour la recherche contre le Cancer (B. M. and M. W.), and l'Interface Chimie-Biologie, CNRS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/20/93. Accepted 11/ 5/93.




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