Polymorphisms of CYP2C8 alter first-electron transfer kinetics and increase catalytic uncoupling

William R. Arnold, Susan Zelasko, Daryl D. Meling, Kimberly Sam, Aditi Das

Research output: Contribution to journalArticlepeer-review


Cytochrome P450 2C8 (CYP2C8) epoxygenase is responsible for the metabolism of over 60 clinically relevant drugs, notably the anticancer drug Taxol (paclitaxel, PAC). Specifically, there are naturally occurring polymorphisms, CYP2C8*2 and CYP2C8*3, that display altered PAChydroxylation rates despite these mutations not being located in the active site. Herein, we demonstrate that these polymorphisms result in a greater uncoupling of PAC metabolism by increasing the amount of hydrogen peroxide formed per PAC turnover. Anaerobic stopped-flow measurements determined that these polymorphisms have altered first electron transfer kinetics, compared to CYP2C8*1 (wildtype), that suggest electron transfer from cytochrome P450 reductase (CPR) is disfavored. Therefore, these data demonstrate that these polymorphisms affect the catalytic cycle of CYP2C8 and suggest that redox interactions with CPR are disrupted.

Original languageEnglish (US)
Article number4626
JournalInternational journal of molecular sciences
Issue number18
StatePublished - Sep 2 2019


  • CYP2C8
  • Cytochrome P450 reductase
  • Electron transfer
  • Paclitaxel
  • Polymorphisms
  • Reactive oxygen species

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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