Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4

J Pharmacol Sci. 2005 Jan;97(1):83-90. doi: 10.1254/jphs.fp0040603. Epub 2005 Jan 15.

Abstract

Paclitaxel is widely used for treatment of malignant tumors. Paclitaxel is metabolized by CYP2C8 and CYP3A4, and these enzymes are known to differ between individuals, although the details have not been clarified. Recent progress in pharmacogenetics has shown that genetic polymorphisms of metabolic enzymes are related to these individual differences. We investigated the effect of the polymorphisms on paclitaxel metabolism by analyzing metabolic activities of CYP2C8 and CYP3A4 and expressions of mRNA and protein. Production of 6alpha-hydroxypaclitaxel, a metabolite of CYP2C8, was 2.3-fold larger than 3'-p-hydroxypaclitaxel, a metabolite of CYP3A4. Significant inter-individual differences between these two enzyme activities were shown. The expressions of mRNA and protein levels correlated well with the enzyme activities, especially with CYP3A4. Although it was previously reported that CYP2C8*3 showed lower activity than the wild type, two subjects that had the CYP2C8*3 allele did not show lower activities in our study. Inter-individual differences in paclitaxel metabolism may be related to CYP2C8 and CYP3A4 mRNA expression. CYP2C8 is the primary metabolic pathway of paclitaxel, but there is a "shifting phenomenon" in the metabolic pathway of paclitaxel in the liver of some human subjects.

Publication types

  • Comparative Study

MeSH terms

  • Alleles
  • Aryl Hydrocarbon Hydroxylases / chemistry
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Blotting, Western / methods
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Gene Expression
  • Genetic Carrier Screening
  • Genotype
  • Humans
  • Individuality
  • Microsomes, Liver / metabolism*
  • Mutation
  • Paclitaxel / chemistry
  • Paclitaxel / metabolism*
  • Paclitaxel / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Species Specificity
  • Taxoids / chemistry
  • Taxoids / metabolism

Substances

  • RNA, Messenger
  • Taxoids
  • 3'-p-hydroxypaclitaxel
  • 6-hydroxytaxol
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Paclitaxel