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Cytochrome P450 Enzymes in the Bioactivation of Polyunsaturated Fatty Acids and Their Role in Cardiovascular Disease

  • Chapter
Book cover Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 851))

Abstract

Various members of the cytochrome P450 (CYP) superfamily have the capacity of metabolizing omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs). In most mammalian tissues, CYP2C and CYP2J enzymes are the major PUFA epoxygenases, whereas CYP4A and CYP4F subfamily members function as PUFA hydroxylases. The individual CYP enzymes differ in their substrate specificities as well as regio- and stereoselectivities and thus produce distinct sets of epoxy and/or hydroxy metabolites, collectively termed CYP eicosanoids. Nutrition has a major impact on the endogenous CYP-eicosanoid profile. “Western diets” rich in n-6 PUFAs result in a predominance of arachidonic acid-derived metabolites, whereas marine foodstuffs rich in n-3 PUFAs shift the profile to eicosapentaenoic and docosahexaenoic acid-derived metabolites. In general, CYP eicosanoids are formed as second messengers of numerous hormones, growth factors and cytokines regulating cardiovascular and renal function, and a variety of other physiological processes. Imbalances in the formation of individual CYP eicosanoids are linked to the development of hypertension, myocardial infarction, maladaptive cardiac hypertrophy, acute kidney injury, stroke and inflammatory disorders. The underlying mechanisms are increasingly understood and may provide novel targets for the prevention and treatment of these disease states. Suitable pharmacological agents are under development and first proofs of concept have been obtained in animal models.

Abbreviations: AA arachidonic acid, ALA alpha-linolenic acid, COX cyclooxygenase, CYP cytochrome P450, DHA docosahexaenoic acid, EDHF endothelium-derived hyperpolarizing factors, EDP epoxydocosapentaenoic acid, EEQ epoxyeicosatetraenoic acid, EET epoxyeicosatrienoic acid, EPA ecosapentaenoic acid, HDoHE hydroxydocosahexaenoic acid, HEPE hydroxyeicosapentaenoic acid, HETE hydroxyeicosatetraenoic acid, HETrE hydroxyeicosatrienoic acid, I/R ischemia-reperfusion, KO knockout, LA linoleic acid, LOX lipoxygenase, PLA2 phospholipase A2, PUFA polyunsaturated fatty acid, ROS reactive oxygen species, sEH soluble epoxide hydrolase, SHR spontaneously hypertensive rat, TAC transverse aortic constriction, TG transgene, WT wild-type.

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Acknowledgments

This review is dedicated to the late John Charles (Jack) McGiff, MD and Professor of Pharmacology. Professor McGiff made seminal discoveries on the role of CYP eicosanoids in blood pressure regulation and he inspired many students and colleagues to follow his way of successfully combining biochemistry and pathophysiology for understanding the mechanisms of complex cardiovascular diseases. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG): Schu822/5; FOR 1054 and Schu822/7-1; FOR 1368.

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  1. Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin, 13125, Germany

    Christina Westphal, Anne Konkel & Wolf-Hagen Schunck

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  1. Christina Westphal
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  2. Anne Konkel
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  3. Wolf-Hagen Schunck
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Correspondence to Wolf-Hagen Schunck .

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Editors and Affiliations

  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Eugene G. Hrycay

  2. Fac. of Pharmaceutical Sciences, The University of British Columbia , Vancouver, British Columbia, Canada

    Stelvio M. Bandiera

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© 2015 Springer International Publishing Switzerland

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Westphal, C., Konkel, A., Schunck, WH. (2015). Cytochrome P450 Enzymes in the Bioactivation of Polyunsaturated Fatty Acids and Their Role in Cardiovascular Disease. In: Hrycay, E., Bandiera, S. (eds) Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450. Advances in Experimental Medicine and Biology, vol 851. Springer, Cham. https://doi.org/10.1007/978-3-319-16009-2_6

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