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Related Experiment Videos

Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid.

D Dai1, D C Zeldin, J A Blaisdell

  • 1Laboratories of Pharmacology and Chemistry and Pulmonary and Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Pharmacogenetics
|October 23, 2001
PubMed
Summary
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New genetic variants of Cytochrome P450 (CYP) 2C8, specifically CYP2C8*2 and CYP2C8*3, impact paclitaxel and arachidonic acid metabolism. The CYP2C8*3 variant shows significant defects, affecting both anticancer drug efficacy and physiological processes.

Area of Science:

  • Pharmacogenomics
  • Enzyme kinetics
  • Molecular biology

Background:

  • Cytochrome P450 (CYP) 2C8 is crucial for metabolizing the anticancer drug paclitaxel and arachidonic acid into epoxyeicosatrienoic acids (EETs).
  • Genetic variations (polymorphisms) in CYP genes can alter enzyme activity, influencing drug response and endogenous compound metabolism.

Purpose of the Study:

  • To identify and characterize novel CYP2C8 genetic variants.
  • To investigate the functional impact of these variants on the metabolism of paclitaxel and arachidonic acid.

Main Methods:

  • Description of two new CYP2C8 alleles: CYP2C8*2 (Ile269Phe) and CYP2C8*3 (Arg139Lys, Lys399Arg).
  • Genotyping to determine allele frequencies in different ethnic groups (African-Americans, Caucasians, Asians).
  • Expression of recombinant CYP2C8 variants (CYP2C8*1, CYP2C8*2, CYP2C8*3) in E. coli for in vitro metabolic assays.

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Main Results:

  • CYP2C8*2 was found in African-Americans (frequency 0.18), and CYP2C8*3 in Caucasians (frequency 0.13); neither in Asians.
  • Recombinant CYP2C8*3 exhibited significantly reduced activity for both paclitaxel (15% of wild-type) and arachidonic acid (35-40% of wild-type) metabolism.
  • CYP2C8*2 showed altered paclitaxel metabolism with a two-fold higher Km and two-fold lower intrinsic clearance compared to wild-type.

Conclusions:

  • The CYP2C8*3 allele is functionally defective in metabolizing both paclitaxel and arachidonic acid.
  • The CYP2C8*2 allele also affects paclitaxel metabolism.
  • These CYP2C8 polymorphisms have significant clinical and physiological implications, particularly for individuals homozygous for CYP2C8*3.