Review
Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids

https://doi.org/10.1016/j.bbapap.2010.09.009Get rights and content

Abstract

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA), such as epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid, serve as second messengers of various hormones and growth factors and play pivotal roles in the regulation of vascular, renal and cardiac function. As discussed in the present review, virtually all of the major AA metabolizing CYP isoforms accept a variety of other polyunsaturated fatty acids (PUFA), including linoleic, eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), as efficient alternative substrates. The metabolites of these alternative PUFAs also elicit profound biological effects. The CYP enzymes respond to alterations in the chain-length and double bond structure of their substrates with remarkable changes in the regio- and stereoselectivity of product formation. The omega-3 double bond that distinguishes EPA and DHA from their omega-6 counterparts provides a preferred epoxidation site for CYP1A, CYP2C, CYP2J and CYP2E subfamily members. CYP4A enzymes that predominantly function as AA ω-hydroxylases show largely increased (ω-1)-hydroxylase activities towards EPA and DHA. Taken together, these findings indicate that CYP-dependent signaling pathways are highly susceptible to changes in the relative bioavailability of the different PUFAs and may provide novel insight into the complex mechanisms that link essential dietary fatty acids to the development of cardiovascular disease.

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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