Elsevier

Pharmacological Reports

Volume 62, Issue 3, May–June 2010, Pages 536-547
Pharmacological Reports

Cytochrome P450–dependent metabolism of ω-6 and ω-3 long-chain polyunsaturated fatty acids

https://doi.org/10.1016/S1734-1140(10)70311-XGet rights and content

Abstract

Dietary fish oil ω-3 fatty acids (n-3 PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against arrhythmia and sudden cardiac death using largely unknown mechanisms. EPA and DHA may serve as efficient alternative substrates of arachidonic acid (AA) metabolizing cytochrome P450 (CYP) enzymes. For many of the CYP isoforms, the n-3 PUFAs are the preferred substrates. Moreover, the CYP enzymes oxygenate EPA and DHA with largely different regioselectivities compared to AA. In particular, the ω-3 double bond that distinguishes EPA and DHA from AA is a preferred site of CYP-catalyzed epoxidation reactions. Given the pivotal role of CYP-dependent AA metabolites in the regulation of vascular, renal and cardiac functions, their replacement by unique sets of epoxy- and hydroxy-metabolites derived from EPA and DHA may have far-reaching physiological implications. The currently available data suggest that some of the vasculo- and cardioprotective effects attributed to dietary n-3 PUFAs may be mediated by CYP-dependent metabolites of EPA and DHA.

Section snippets

Cardiovascular protective effects of ω-3 fatty acids

Polyunsaturated fatty acids (PUFAs) of both the ω-6 (n-6) and ω-3 (n-3) class are essential dietary components because they are necessary for human health but cannot be synthesized de novo in the body. The genetic constitution of human beings likely evolved on a diet with a ratio of n-6 to n-3 PUFAs of about 1:1, whereas in recent Western diets, the typical ratio is 15:1 [80]. The general hypothesis that this imbalance increases the susceptibility to cardiovascular and other chronic diseases

Role of cytochrome P450-dependent arachidonic acid metabolites in the cardiovascular system

AA is oxygenated by COX, LOX and CYP enzymes to different classes of biologically active metabolites collectively termed eicosanoids. COX enzymes initiate the formation of prostaglandins and thromboxanes and LOX enzymes form leukotrienes and lipoxins [21]. These metabolites activate rhodopsin-like seven membrane-spanning G-protein coupled receptors (GPCRs) [28, 69]. The COX- and LOX-dependent pathways are clinically targeted in the treatment of inflammation, cardiovascular disease, asthma,

Cytochrome P450-dependent metabolism of EPA and DHA

EPA and DHA can partially replace AA at the sn-2 position of glycerophospholipids and may become accessible to CYP enzymes in the same way as AA after extracellular signal-induced activation of phospholipases (Fig. 1). However, the possibility that EPA and DHA may indeed serve as alternative substrates of AA metabolizing CYP isoforms has been recognized only recently. Early studies performed in the 1980s revealed that liver and renal microsomal CYP enzymes convert EPA and DHA, like AA, by

Conclusions and hypothesis on the physiological implications

The studies described above demonstrate that the CYP isoforms involved in the production of physiologically active AA metabolites accept EPA and DHA as efficient alternative substrates. Several of the enzymes show higher catalytic rates when converting EPA or DHA instead of AA. Important examples for a preference towards EPA involve CYP2J2, the major EET producing isoform in the human heart, CYP2C23, the predominant EET producing isoform in the rat kidney and Cyp4a12a, the mouse renal

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