Hydrogen peroxide inhibits cytochrome P450 epoxygenases: Interaction between two endothelium-derived hyperpolarizing factors

Brandon T. Larsen, David D. Gutterman, Atsushi Sato, Kazuyoshi Toyama, William B. Campbell, Darryl C. Zeldin, Vijay L. Manthati, John R. Falck, Hiroto Miura

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

The cytochrome P450 epoxygenase (CYP)-derived metabolites of arachidonic acid the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H2O2) both function as endothelium-derived hyperpolarizing factors (EDHFs) in the human coronary microcirculation. However, the relative importance of and potential interactions between these 2 vasodilators remain unexplored. We identified a novel inhibitory interaction between CYPs and H2O2 in human coronary arterioles, where EDHF-mediated vasodilatory mechanisms are prominent. Bradykinin induced vascular superoxide and H2O2 production in an endothelium-dependent manner and elicited a concentration-dependent dilation that was reduced by catalase but not by 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE), 6-(2-propargyloxyphenyl)hexanoic acid, sulfaphenazole, or iberiotoxin. However, in the presence of catalase, an inhibitory effect of these compounds was unmasked. In a tandem-bioassay preparation, application of bradykinin to endothelium-intact donor vessels elicited dilation of downstream endothelium-denuded detectors that was partially inhibited by donor-applied catalase but not by detector-applied EEZE; however, EEZE significantly inhibited dilation in the presence of catalase. EET production by human recombinant CYP 2C9 and 2J2, 2 major epoxygenase isozymes expressed in human coronary arterioles, was directly inhibited in a concentration-dependent fashion by H2O2 in vitro, as observed by high-performance liquid chromatography (HPLC); however, EETs were not directly sensitive to oxidative modification. H2O2 inhibited dilation to arachidonic acid but not to 11,12-EET. These findings suggest that an inhibitory interaction exists between 2 EDHFs in the human coronary microcirculation. CYP epoxygenases are directly inhibited by H2O2, and this interaction may modulate vascular EET bioavailability.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalCirculation research
Volume102
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Cytochrome P450
  • Endothelium-derived hyperpolarizing factor
  • Epoxyeicosatrienoic acid
  • Hydrogen peroxide
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Larsen, B. T., Gutterman, D. D., Sato, A., Toyama, K., Campbell, W. B., Zeldin, D. C., Manthati, V. L., Falck, J. R., & Miura, H. (2008). Hydrogen peroxide inhibits cytochrome P450 epoxygenases: Interaction between two endothelium-derived hyperpolarizing factors. Circulation research, 102(1), 59-67. https://doi.org/10.1161/CIRCRESAHA.107.159129