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Selective Biotransformation of Taxol to 6-Hydroxytaxol by Human Cytochrome P450 2C8¹

Divisions of Biopharmaceutics and of Clinical Pharmacology, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland 20857 [A. R., J. W. H.], Laboratory of Molecular Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892 [K. R. K., J. G., F. J. G.]

The principal taxol biotransformation reaction of humans and of human hepatic in vitro preparations is 6-hydroxylation of the taxane ring, but a separate, minor hydroxylation pathway (metabolite B formation) also exists. Taxol metabolism was studied using membrane fractions from Hep G₂ cells infected with recombinant vaccinia viruses that contain complementary DNAs encoding several human cytochrome P450 enzymes. Only P450 2C8 formed detectable 6-hydroxytaxol. Metabolite B formation was catalyzed by complementary DNA-expressed 3A3 and 3A4, but not by 3A5. Each P450 3A preparation catalyzed felodipine oxidation. The apparent K_m and V_max values for taxol 6-hydroxylation were 5.4 ± 1.0 µM and 30 ± 1.5 nmol/min/nmol P450, respectively, for complementary DNA-expressed P450 2C8; the values were 4.0 ± 1.0 µM and 0.87 ± 0.06 nmol/min/mg protein, respectively, for human hepatic microsomes. The inhibition of 6-hydroxytaxol formation by quercetin was competitive with an apparent K_i of 1.3 or 1.1 µM with 2C8 or hepatic microsomes, respectively; retinoic acid was inhibitory, showing an apparent K_i of 27 µM with hepatic microsomes; inhibition by tolbutamide was complex, weak, and unlikely to be clinically relevant. The correlation between hepatic 2C8 protein content and 6-hydroxytaxol formation was high (r² = 0.82), while the correlation with 2C9 content was low (r² = 0.38).

These data show that human biotransformation routes of taxol result from catalysis by specific enzymes of two P450 families and that taxol 6-hydroxylation is a useful indicator of P450 2C8 activity in human hepatic microsomes.

¹ The United States Adopted Name Council has assigned the name "paclitaxel" to taxol and TAXOL.

² To whom requests for reprints should be addressed, at FDA/CDER/ORR/DCP, 8301 Muirkirk Road, Laurel, MD 20708.

Received 9/ 6/94. Accepted 9/28/94.

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