Cytochrome P450 3A-mediated human liver microsomal taxol 6 alpha-hydroxylation.
The antitumor drug taxol was metabolized to one major (6 alpha-hydroxytaxol) and two minor metabolites by human liver microsomes. A 10-fold interindividual variability with a Vmax of 1.16 +/- 0.85 nmol/hr/mg of microsomal protein and a Km of 18.0 +/- 12.2 microM was observed for taxol 6 alpha-hydroxylation (mean +/- S.D.; n = 6). The NADPH-dependency and the inhibitory effect of carbon monoxide and piperonyl butoxide on taxol metabolism indicated the involvement of cytochrome P450 (CYP) monooxygenases. Chemical inhibition studies pointed to the CYP 3A subfamily as being responsible for taxol 6 alpha-hydroxylation. However, although some CYP 3A substrates were inhibitory (midazolam, 17 alpha-ethinyl estradiol, quercetin, verapamil and testosterone), others were not (troleandomycin, erythromycin and cyclosporin A). The inhibition was found to be competitive with low Ki values for midazolam (10.5 microM) and 17 alpha-ethinyl estradiol (4.5 microM). Taxol 6 alpha-hydroxylation correlated well with the metabolism of 17 alpha-ethinyl estradiol (r = 0.874; P < .05) and midazolam (r = 0.954; P < .01) in the same livers. Rabbit anti-rat CYP 3A1 antibodies, which cross-react with human CYP 3A isoforms, were inhibitory of taxol 6 alpha-hydroxylation. Although the evidence from these experiments supported the CYP 3A mediation of taxol 6 alpha-hydroxylation, the lack of effect of some inhibitors combined with the inability of a human CYP 3A4 transfected cell line to metabolize taxol point to a CYP 3A isoform other than 3A4. The findings in this study could prove clinically useful for the prediction of potential drug interactions, both inhibitory and inductive of taxol metabolism.
Kumar
G N
GN
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston.
Walle
U K
UK
Walle
T
T
D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007106:Immune Sera; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043823:Taxoids
D007106:Immune Sera; D043823:Taxoids; C086219:6-hydroxytaxol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D017239:Paclitaxel