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