Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of {omega}-3 fatty acids.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect against cardiovascular disease by largely unknown mechanisms. We tested the hypothesis that EPA and DHA may compete with arachidonic acid (AA) for the conversion by cytochrome P450 (CYP) enzymes, resulting in the formation of alternative, physiologically active, metabolites. Renal and hepatic microsomes, as well as various CYP isoforms, displayed equal or elevated activities when metabolizing EPA or DHA instead of AA. CYP2C/2J isoforms converting AA to epoxyeicosatrienoic acids (EETs) preferentially epoxidized the ω-3 double bond and thereby produced 17,18-epoxyeicosatetraenoic (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from EPA and DHA. We found that these ω-3 epoxides are highly active as antiarrhythmic agents, suppressing the Ca(2+)-induced increased rate of spontaneous beating of neonatal rat cardiomyocytes, at low nanomolar concentrations. CYP4A/4F isoforms ω-hydroxylating AA were less regioselective toward EPA and DHA, catalyzing predominantly ω- and ω minus 1 hydroxylation. Rats given dietary EPA/DHA supplementation exhibited substantial replacement of AA by EPA and DHA in membrane phospholipids in plasma, heart, kidney, liver, lung, and pancreas, with less pronounced changes in the brain. The changes in fatty acids were accompanied by concomitant changes in endogenous CYP metabolite profiles (e.g. altering the EET/EEQ/EDP ratio from 87:0:13 to 27:18:55 in the heart). These results demonstrate that CYP enzymes efficiently convert EPA and DHA to novel epoxy and hydroxy metabolites that could mediate some of the beneficial cardiovascular effects of dietary ω-3 fatty acids.
Arnold
Cosima
C
From the Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
Markovic
Marija
M
From the Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
Blossey
Katrin
K
Lipidomix GmbH, 13125 Berlin, Germany.
Wallukat
Gerd
G
From the Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
Fischer
Robert
R
Experimental and Clinical Research Center, Charité Medical Faculty, 13125 Berlin, Germany.
Dechend
Ralf
R
Experimental and Clinical Research Center, Charité Medical Faculty, 13125 Berlin, Germany.
Konkel
Anne
A
From the Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
von Schacky
Clemens
C
Omegametrix GmbH, 82152 Martinsried, Germany.
Luft
Friedrich C
FC
From the Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany; Experimental and Clinical Research Center, Charité Medical Faculty, 13125 Berlin, Germany.
Muller
Dominik N
DN
From the Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
Rothe
Michael
M
Lipidomix GmbH, 13125 Berlin, Germany.
Schunck
Wolf-Hagen
WH
From the Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: schunck@mdc-berlin.de.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium; D002318:Cardiovascular Diseases / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D007527:Isoenzymes; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D015118:Eicosapentaenoic Acid; D002118:Calcium