Cytochrome P450-dependent metabolism of eicosapentaenoic acid in the nematode Caenorhabditis elegans

Kulas, Jana; Schmidt, Carolin; Rothe, Michael; Schunck, Wolf‐Hagen; Menzel, Ralph

doi:10.1016/j.abb.2008.02.002

Cited by 69 publications

(94 citation statements)

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“…EPA and AA are the main C20-PUFAs in C. elegans, whereby EPA represents about 30 % and AA about 5 % of total fatty acids [17]. As exemplified in the present study by the fat-2 and fat-3 mutant strains, any inability of synthesising C20-PUFAs is associated with impaired locomotion activity already under normoxic conditions and a lack of the O2-ON response to anoxia/reoxygenation.…”

Section: Discussionsupporting

confidence: 55%

“…The nematodes were grown at 20°C on NGM (nematode growth medium) agar plates inoculated with Escherichia coli OP50 as food source [19] and were incubated under similar conditions as described before [17].…”

Section: Nematode Strain and Cultivation Conditionmentioning

confidence: 99%

“…EPA (eicosapentaenoic acid; C 20:5, n−3 ) and AA are the main PUFAs in the wild-type strain, whereas neither EPA nor AA can be synthesized in the desaturase-deficient mutants. Concomitantly, only the wild-type, but not the fat-2 and fat-3 mutants, contain EPA-and AA-derived epoxy and hydroxy metabolites as produced by CYP monooxygenases when metabolizing these C20-PUFAs [17,18]. We reported previously that also the EGL-9 deficient strain displayed very low levels of free CYP-eicosanoids and that this deficiency was partially overcome by the gain-of-function mutation in the cyp-13A12 gene [5].…”

mentioning

confidence: 98%

“…To ensure anoxia conditions during the process of harvest as long as possible, liquid nitrogen was carefully filled at the bottom of the anoxia chamber, but without freezing the agar inside the Petri dishes. Then, nematodes were washed with ice-cold M9 buffer from the plates and prepared for LC-MS/MS analysis essentially as described previously [17,18]. …”

mentioning

confidence: 99%

“…CYP2J2 overexpression also protects against hypoxia-reoxygenation injury in cultured endothelial 12 cells [36]. Most recently, CYP2J2 was shown to exert marked neuroprotective effects in a mouse model of cerebral ischemia [37].EPA and AA are the main C20-PUFAs in C. elegans, whereby EPA represents about 30 % and AA about 5 % of total fatty acids [17]. As exemplified in the present study by the fat-2 and fat-3 mutant strains, any inability of synthesising C20-PUFAs is associated with impaired locomotion activity already under normoxic conditions and a lack of the O2-ON response to anoxia/reoxygenation.…”

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confidence: 99%

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CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Keller

Ellieva

Dengke

et al. 2014

Biochemical Journal

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SHORT TITLE:CYP-13A12 of C. elegans is a PUFA-epoxygenase 4 SYNOPSISA specific behavioural response of Caenorhabditis elegans, the rapid increase of locomotion in response to anoxia/reoxygenation called the O2-ON response, has been used to model key aspects of ischemia/reperfusion injury. A genetic suppressor screen demonstrated a direct causal role of CYP-13A12 in this response and suggested that CYP-eicosanoids, which in mammals influence the contractility of cardiomyocytes and vascular smooth muscle cells, might function in C. elegans as specific regulators of the body muscle cell activity. Here we show that co-expression of CYP-13A12 with the NADPH-CYP-reductase EMB-8 in insect cells resulted in the reconstitution of an active microsomal monooxygenase system that metabolised EPA (eicosapentaenoic acid) and also AA (arachidonic acid) to specific sets of regioisomeric epoxy and hydroxy derivatives. Main products included 17,18-EEQ (epoxyeicosatetraenoic acid) from EPA and 14,15-EET (epoxyeicosatrienoic acid) from AA. Locomotion assays showed that the defective O2-ON response of C20-PUFA-deficient, ∆ -12 and ∆ -6 fatty acid desaturase mutants (fat-2 and fat-3, respectively) can be restored by feeding the nematodes AA or EPA, but not ETYA (eicosatetraynoic acid), a non-metabolisable AAanalogue. Already short-term incubation with 17,18-EEQ was sufficient to rescue the impaired locomotion of the fat-3 strain. The endogenous level of free 17,18-EEQ declined during anoxia and was rapidly restored in response to reoxygenation. Based on these results, we suggest that CYP-dependent eicosanoids such as 17,18-EEQ function as signalling molecules in the regulation of the O2-ON response in C. elegans. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity already under normoxic conditions and was effective not only with C20-PUFA mutants but to a lesser extent also with wild-type worms. KEYWORDS:Eicosanoids; Polyunsaturated fatty acids; Caenorhabditis elegans; Cytochrome P450; Reoxygenation; 17,18-EEQ ABBREVIATIONS USED: AA, arachidonic acid; CID, collision-induced dissociation; COD, carbon monoxide difference; CPR, NADPH-CYP reductase; CYP, cytochrome P450; DiHETE, dihydroxyeicosatetraenoic acid; DTT, dithiothreitol; EGL, egg laying defect; EGLN, EGL nine; EEQ, epoxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; ETYA, eicosatetraynoic acid; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; HEET, hydroxyepoxyeicosatrienoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HIF, hypoxia inducible factor; LC, liquid chromatography; MC, pharyngeal marginal cell; MS, mass spectrometry; NGM, nematode growth medium; PUFA, polyunsaturated fatty acid; RP, reversed-phase 5 INTRODUCTIONOxygen deprivation upon restriction of blood supply followed by reperfusion and concomitant reoxygenation causes tissue injury and is involved in the initiation of various human pathologies including ischemic stroke, myocardial infarction, and ac...

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Section: Discussionsupporting

confidence: 55%

Section: Nematode Strain and Cultivation Conditionmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Keller

Ellieva

Dengke

et al. 2014

Biochemical Journal

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Applications of iRNA Technologies in Drug Transporters and Drug Metabolizing Enzymes

Liao

Xia

2012

ADME‐Enabling Technologies in Drug Design and Development

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CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan

Lim,

Pan,

Alshagga

et al. 2024

J of Applied Toxicology

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CYP‐14 members of the Caenorhabditis elegans (C. elegans) Cytochrome P450 (CYP) enzyme family, plays important roles in mitochondrial dysfunction, detoxification, lipid metabolism, defense and lifespan regulation. The review identifies CYP‐14 members: cyp‐14A1, cyp‐14A2, cyp‐14A3, cyp‐14A4, cyp‐14A5 and their homology with human CYP families. Despite limited studies on C. elegans cyp‐14 members, the findings unraveled their complex crosstalk between mitochondrial stress, detoxification mechanisms, and lifespan regulation, emphasizing the complexity of these interconnected pathways as well as how their regulation depends on environmental cues changes including pH, nutrients, ROS and chemical stressors. The review underscores the translational relevance to human health, shedding light on potential human homologues and their implications in age‐related, metabolic and respiratory diseases. Among other genes, cyp‐14A2 and cyp‐14A4 predominate the mitochondrial function, heat resistance, lipid metabolism, detoxification and lifespan pathways. In conclusion, these insights pave the way for future research, offering promising avenues for therapeutic interventions targeting CYP‐14 activity to address age‐related diseases and promote healthy aging.

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Cytochrome P450-dependent metabolism of eicosapentaenoic acid in the nematode Caenorhabditis elegans

Cited by 69 publications

References 54 publications

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Applications of iRNA Technologies in Drug Transporters and Drug Metabolizing Enzymes

CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan

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