Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewRole of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids
Research Highlights
► Cytochrome P450 enzymes produce physiologically active arachidonic acid metabolites. ► Linoleic, eicosapentaenoic and docosahexaenoic acid are efficient alternative substrates. ► Unique metabolites of omega-3 fatty acids show cardiovascular protective properties. ► Dietary fatty acids have a major impact on the endogenous CYP metabolite profile.
Section snippets
Introduction: Essential fatty acids and cardiovascular disease
Studies performed for at least 50 years revealed that the amount and quality of dietary fat is one of the most important modifiable risk factors for the development of cardiovascular disease [1], [2]. Recent recommendations focus on the use of diets low in saturated fatty acids, almost devoid of trans-fatty acids and rich in n−6 and n−3 polyunsaturated fatty acids (PUFAs) [3], [4], [5]. An appropriate balance in the nutritional uptake of n−6 and n−3 PUFAs is of particular importance because they
Primary products and CYP isoforms involved in arachidonic acid metabolism
CYP enzymes function as monooxygenases and metabolize AA by catalyzing hydroxylation, epoxidation or allylic oxidation reactions [14], [42], [43].
Hydroxylation of AA forms a series of regioisomeric hydroxyeicosatetraenoic acids (HETEs). 16-, 17-, 18- and 19-HETE (the “subterminal HETEs”) contain an asymmetric carbon atom and can thus occur as R- or S-enantiomers. CYP enzymes belonging to the CYP4A and CYP4F subfamilies predominantly hydroxylate the terminal methyl-group of AA and are the major
Primary products and CYP isoforms involved in eicosapentaenoic and docosahexaenoic acid metabolism
Studies performed in the 1980s revealed that liver and renal microsomal CYP enzymes convert EPA and DHA, like AA, by epoxidation and hydroxylation [185], [186]. The principal CYP-dependent metabolites derived from EPA include ω/(ω-1)-hydroxyeicosapentaenoic acids (19- and 20-HEPE) and 5 regioisomeric epoxyeicosatetraenoic acids (EEQs; Fig. 4). DHA can be metabolized to ω/(ω-1)-hydroxydocosahexaenoic acids (21- and 22-HDoHE) and 6 regioisomeric epoxydocosapentaenoic acids (EDPs). Recent studies
Conclusions
In the last three decades, much effort has been made to elucidate the mechanisms of synthesis and action of CYP-dependent AA metabolites in the cardiovascular system. These studies revealed pivotal functions of EETs and 20-HETE in the regulation of vascular, renal and cardiac function and raised great expectations that the CYP-branch of the AA cascade can be therapeutically targeted to treat cardiovascular disease [134]. As described in this review, virtually all CYP isoforms involved in AA
Acknowledgements
Both authors have been supported by a grant from the Deutsche Forschungsgemeinschaft (SCHU 822/5). This review is dedicated to Prof. Dr. Klaus Ruckpaul on the occasion of his 80th birthday. Prof. Ruckpaul successfully established the research on cytochrome P450 enzymes in Berlin-Buch and has inspired many of his students and colleagues with his ideas and his passion for science.
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