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Published on: October 27, 2014

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

A Soyama1, Y Saito, N Hanioka

  • 1Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.

Biological & Pharmaceutical Bulletin
|January 5, 2002
PubMed

Insights

Researchers identified novel genetic variations in the CYP2C8 gene, impacting paclitaxel metabolism. These findings reveal that specific CYP2C8 variants, including a new one, reduce the efficiency of processing this important chemotherapy drug.

Area of Science:

  • Pharmacogenomics
  • Molecular Biology
  • Drug Metabolism

Background:

  • The CYP2C8 gene encodes a crucial enzyme involved in drug metabolism.
  • Genetic variations (polymorphisms) in CYP2C8 can alter its function and affect drug efficacy and toxicity.
  • Understanding these variations is vital for personalized medicine, particularly for drugs like paclitaxel.

Purpose of the Study:

  • To identify and characterize single nucleotide polymorphisms (SNPs) in the CYP2C8 gene within a Japanese population.
  • To investigate the functional impact of identified CYP2C8 variants on paclitaxel metabolism.
  • To evaluate the efficiency of novel and known CYP2C8 variants in metabolizing paclitaxel.

Main Methods:

  • Genomic DNA sequencing of 73 Japanese cell lines to detect CYP2C8 SNPs.
  • Site-directed mutagenesis to create variant CYP2C8 cDNA constructs (R139K, K399R, R139K/K399R, P404A).
  • Transfection of wild-type and variant CYP2C8 constructs into Hep G2 cells and in vitro determination of paclitaxel 6a-hydroxylase activity.

Main Results:

  • Nine SNPs were identified in the CYP2C8 gene, with three resulting in amino acid alterations: R139K, K399R, and P404A.
  • The double variant R139K/K399R (CYP2C8*3) exhibited reduced Vmax and clearance, similar to the single R139K variant.
  • The novel P404A variant demonstrated significantly lowered clearance due to reduced protein expression levels.

Conclusions:

  • The study identified novel functional variants in the CYP2C8 gene, including P404A.
  • Both the known CYP2C8*3 variant and the novel P404A variant exhibit reduced efficiency in paclitaxel metabolism.
  • These findings highlight the importance of CYP2C8 genetic variations in influencing paclitaxel pharmacokinetics and suggest potential implications for patient response to this chemotherapy agent.

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