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Cytochrome P450–dependent metabolism of ω-6 and ω-3 long-chain polyunsaturated fatty acids
Abstract
Dietary fish oil omega-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 omega-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.
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“Both EPA and DHA are also precursors to bioactive lipid metabolites, including specialized proresolving mediators36 and cytochrome P450–generated monoepoxides,37 that could contribute to lower CHD risk.”
From ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies (2016) · cites this paper as [37]
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Epoxyeicosatrienoic Acid Pathway in Human Health and Diseases
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Role of Soluble Epoxide Hydrolase in Metabolism of PUFAs in Psychiatric and Neurological Disorders
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“…bioactive derivatives by the main enzymes such as cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs) (Imig and Hammock, 2009; Arnold et al., 2010; Imig, 2012, 2018; Morisseau and Hammock, 2013; Bazinet and Layé, 2014; Urquhart et al., 2015; Westphal et al., 2015; Figure 1).”
BackgroundCytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization
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ω-3 and ω-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases
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Fatty liver induced by free radicals and lipid peroxidation
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Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease
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“P450 also targets the x -3 double bond of DHA, with a higher catalytic ef fi ciency than arachidonic acid (Arnold et al., 2010a), and produces EDPs (Fer et al., 2008; Arnold et al., 2010b).”
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“…conversion to bioactive docosanoids such as resolvins, docosatrienes, and neuroprotectins by enzymes such as 15-LOX, and by other metabolic pathways (Gavino and Gavino 1991; Robinson et al. 1992; Hong et al. 2003; Gleissman et al. 2010; Arnold et al. 2010; Bazan et al. 2010; Groeger et al. 2010).”
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“The first double bond on C3, present in omega-3 but not omega-6, is a preferred site of epoxidation catalyzed by CYP450 [76].”
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Exploring the role of LC-PUFA metabolism in pregnancy complications
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“The adverse health effects of excess dietary omega-6 PUFAs may be mediated by eicosanoids, which are powerful shortlived signaling molecules produced from 20-carbon polyunsaturated fatty acids (PUFAs) through a series of oxidation reactions.”
BackgroundInfluentialSoluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain
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Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia
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Eicosanoid formation by a cytochrome P450 isoform expressed in the pharynx of Caenorhabditis elegans
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“The CYP450-dependent DHA metabolites include the epoxydocosapentaenoic acid (EpDPE) regioisomers 4,5-, 7,8-, 10,11-, 13,14-, 16,17-, and 19,20-EpDPE (4, 6, 22).”
BackgroundLi, M., Li, Z., & Fan, Y. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1598588 · Cited by 34
“The cytochrome P450 pathway refers to the cardioprotective effects of EPA and DHA as effective replacement substrates for the metabolism of cytochrome P450 (CYP) enzymes in arachidonic acid (AA) (54), which simultaneously regulates vasodilation and cerebral blood flow (55).”
Angiogenesis and vascular stability in eicosanoids and cancer
Hu, J., Frömel, T., & Fleming, I. (2018) · Cancer and Metastasis Reviews · doi:10.1007/s10555-018-9732-2 · Cited by 31
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“Cytochrome enzymes, for example, use both n-3 and n-6 FA as substrates but, with increasing concentrations of n-3 FA, will sometimes favor EPA over ARA as a substrate (Arnold et al., 2010).”
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Is multiple sclerosis a proresolution deficiency disorder?
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“…cyp-35 family), similarly as in fish and insects (Nelson, 2003; Feyereisen, 2006), indicating an evolutionally old distinction between the major CYP clades, probably due to their early separated endogenous functions, which in human include metabolism of fatty acid derivatives (Arnold et al., 2010).”
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“The CYP4 and higher numbered families are involved in the metabolism of a diverse range of endogenous compounds including eicosanoids, fatty acids, steroids and vitamins (Spector, 2009; Arnold et al, 2010; Panigrahy et al, 2010; Fleming, 2011; Guengerich and Cheng, 2011; Niwa et al, 2011).”
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“Epoxy fatty acids (EpFAs), such as epoxyeicosatrienoic acids (EETs) derived from arachidonic acid, are important lipid mediators that have pathophysiological significance in the cardiovascular system (Arnold et al., 2010).”
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New Therapies of Neovascular AMD—Beyond Anti-VEGFs
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“CYP4A and 4F subfamilies have been identified as the main P450s for 20-HETE production (Lasker et al. 2000; Pearson et al. 2009), although multiple studies showed that CYP1A1 hydroxylases ARA to 20-HETE Retention Time (min) (Aboutabl et al. 2009; Arnold et al. 2010).”
Metadata
- Authors
- Arnold, C., Konkel, A., Fischer, R., & Schunck, W.-H.
- Affiliations
- Max Delbrück Center (DE)
- Corresponding author
- Schunck, Wolf-Hagen
- Venue
- Pharmacological Reports
- Published
- 2010-05
- Volume
- 62
- Issue
- 3
- Pages
- 536-547
- ISSN
- 1734-1140 (ISSN-L)
- OpenAlex
- W1998719368
- Cited by
- 174
- References
- 111
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 6 · 2023: 13 · 2022: 9 · 2021: 8 · 2020: 10 · 2019: 10 · 2018: 12 · 2017: 13 · 2016: 10 · 2015: 11 · 2014: 19 · 2013: 12 · 2012: 15
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacological Reports (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
- Keywords
- cytochrome P450, omega-3 fatty acids, omega-6 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid metabolism, fatty acid epoxidation, regioselectivity, epoxy fatty acids, hydroxy fatty acids, fish oil, cardioprotection, vascular protection, sudden cardiac death, cardiac arrhythmias
- MeSH terms
- Cytochrome P-450 CYP2J2, Animals, Cardiotonic Agents, Cardiovascular Diseases, Cytochrome P-450 Enzyme System, Docosahexaenoic Acids, Epoxide Hydrolases, Humans, Hydroxyeicosatetraenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Arachidonic Acid, Death, Sudden, Cardiac, Cytochrome P-450 CYP1A1, Cytochrome P-450 CYP2E1, Fatty Acids, Omega-6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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