Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism

Biol Pharm Bull. 2001 Dec;24(12):1427-30. doi: 10.1248/bpb.24.1427.


By sequencing genomic DNA from 73 established cell lines derived from Japanese individuals, we detected 9 single nucleotide polymorphisms (SNPs) in the CYP2C8 gene. Of them, 3 exonic SNPs resulted in amino acid alterations (g416a, R139K; a1196g, K399R; c1210g, P404A). The first two alterations were detected concurrently in one cell line and thought to be the same as CYP2C8*3. To examine the effects of these amino acid alterations on CYP2C8 function, wild-type and four types of variant CYP2C8 cDNA constructs (R139K, K399R, R139K/K399R and P404A) were transfected into Hep G2 cells and their paclitaxel 6a-hydroxylase activities were determined in vitro. Km values were not significantly different from that of the wild-type in any of the variants studied. The variant R139K/K399R showed reduced values for Vmax and clearance (Vmax/Km) similar to those of its single variant, R139K. The variant P404A also showed a significantly lowered clearance due to reduced level of protein expression. These results suggest that not only the double variant (R139K/K399R, CYP2C8*3) but also our novel variant P404A in the CYP2C8 gene are less efficient in paclitaxel metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Antineoplastic Agents, Phytogenic / metabolism
  • Aryl Hydrocarbon Hydroxylases*
  • Cell Line
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Activation
  • Humans
  • Paclitaxel / metabolism*
  • Polymorphism, Single Nucleotide / genetics*
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / genetics*
  • Steroid Hydroxylases / metabolism
  • Transfection
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Phytogenic
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Steroid 16-alpha-Hydroxylase
  • Paclitaxel