Isolation, structural determination, and biological activity of 6 alpha-hydroxytaxol, the principal human metabolite of taxol

J Med Chem. 1994 Mar 4;37(5):706-9. doi: 10.1021/jm00031a022.

Abstract

The principal biotransformation product of taxol was found to be identical for human hepatic microsomes, human liver slices, and patient bile samples. We have isolated this metabolite from the bile of a patient given taxol, and we report its structure and its cytotoxicity relative to taxol. The NMR and SIMS data presented here indicate that, in humans, taxol is regiospecifically hydroxylated at the 6-position on the taxane ring and that this hydroxyl is stereospecifically placed trans to the hydroxyl at position 7, yielding 6 alpha-hydroxytaxol. This metabolite is apparently not formed in rats. Tests of the growth inhibition potential of 6 alpha-hydroxytaxol versus taxol in two human tumor cell lines showed that the metabolite was approximately 30-fold less cytotoxic than taxol. Thus the cytochrome P-450-mediated biotransformation of taxol to 6 alpha-hydroxytaxol can be classified as a detoxification reaction.

Publication types

  • Comparative Study

MeSH terms

  • Bile / chemistry
  • Cell Division / drug effects
  • Cell Line
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Hydroxylation
  • Inactivation, Metabolic
  • Liver / chemistry
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Paclitaxel / analogs & derivatives*
  • Paclitaxel / chemistry
  • Paclitaxel / isolation & purification
  • Paclitaxel / pharmacokinetics*
  • Paclitaxel / pharmacology
  • Taxoids*

Substances

  • Taxoids
  • 6-hydroxytaxol
  • Cytochrome P-450 Enzyme System
  • Paclitaxel