Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2C subfamily

Eduardo Barbosa-Sicard; Marija Markovic; Horst Honeck; Baghat Christ; Dominik N Muller; Wolf-Hagen Schunck

doi:10.1016/j.bbrc.2005.02.103

Eicosapentaenoic acid metabolism by cytochrome P450 enzymes of the CYP2C subfamily

Biochem Biophys Res Commun. 2005 Apr 22;329(4):1275-81. doi: 10.1016/j.bbrc.2005.02.103.

Authors

Eduardo Barbosa-Sicard¹, Marija Markovic, Horst Honeck, Baghat Christ, Dominik N Muller, Wolf-Hagen Schunck

Affiliation

¹ Max Delbrück Center for Molecular Medicine, Berlin, Germany.

PMID: 15766564
DOI: 10.1016/j.bbrc.2005.02.103

Abstract

CYP2C enzymes epoxidize arachidonic acid (AA) to metabolites involved in the regulation of vascular and renal function. We tested the hypothesis that eicosapentaenoic acid (EPA), a n-3 polyunsaturated fatty acid, may serve as an alternative substrate. Human CYP2C8 and CYP2C9, as well as rat CYP2C11 and CYP2C23, were co-expressed with NADPH-CYP reductase in a baculovirus/insect cell system. The recombinant enzymes showed high EPA and AA epoxygenase activities and the catalytic efficiencies were almost equal comparing the two substrates. The 17,18-double bond was the preferred site of EPA epoxidation by CYPs 2C8, 2C11, and 2C23. 17(R),18(S)-Epoxyeicosatetraenoic acid was produced with an optical purity of about 70% by CYPs 2C9, 2C11, and 2C23 whereas CYP2C8 showed the opposite enantioselectivity. These results demonstrate that EPA is an efficient substrate of CYP2C enzymes and suggest that n-3 PUFA-rich diets may shift the CYP2C-dependent generation of physiologically active eicosanoids from AA- to EPA-derived metabolites.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aryl Hydrocarbon Hydroxylases / metabolism
Catalysis
Cell Line
Chromatography, High Pressure Liquid
Cytochrome P-450 CYP2C8
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2J2
Cytochrome P-450 Enzyme System / classification*
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism*
Cytochrome P450 Family 2
Eicosapentaenoic Acid / chemistry
Eicosapentaenoic Acid / metabolism*
Humans
Kinetics
Protein Isoforms / classification
Protein Isoforms / genetics
Protein Isoforms / metabolism
Rats
Spodoptera
Stereoisomerism
Steroid 16-alpha-Hydroxylase / metabolism
Substrate Specificity

Substances

Cyp2c23 protein, rat
Protein Isoforms
cytochrome P-450 CYP2C subfamily
Cytochrome P-450 Enzyme System
Eicosapentaenoic Acid
CYP2C9 protein, human
Cytochrome P-450 CYP2C9
Aryl Hydrocarbon Hydroxylases
CYP2C11 protein, rat
CYP2C8 protein, human
Cytochrome P-450 CYP2C8
Cytochrome P-450 CYP2J2
Cytochrome P450 Family 2
Steroid 16-alpha-Hydroxylase