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

Item Type:Article
Title:Cytochrome P450-dependent metabolism of eicosapentaenoic acid in the nematode Caenorhabditis elegans
Creators Name:Kulas, J. and Schmidt, C. and Rothe, M. and Schunck, W.H. and Menzel, R.
Abstract:The genome of Caenorhabditis elegans contains 75 full length cytochrome P450 (CYP) genes whose individual functions are largely unknown yet. We tested the hypothesis that some of them may be involved in the metabolism of eicosapentaenoic acid (EPA), the predominant polyunsaturated fatty acid of this nematode. Microsomes isolated from adult worms contained spectrally active CYP proteins and showed NADPH-CYP reductase (CPR) activities. They metabolized EPA and with lower activity also arachidonic acid (AA) to specific sets of regioisomeric epoxy- and omega-/(omega-1)-hydroxy-derivatives. 17(R),18(S)-epoxyeicosatetraenoic acid was produced as the main EPA metabolite with an enantiomeric purity of 72%. The epoxygenase and hydroxylase reactions were NADPH-dependent, required the functional expression of the CPR-encoding emb-8 gene, and were inhibited by 17-ODYA and PPOH, two compounds known to inactivate mammalian AA-metabolizing CYP isoforms. Multiple followed by single RNAi gene silencing experiments identified CYP-29A3 and CYP-33E2 as the major isoforms contributing to EPA metabolism in C. elegans. Liquid chromatography/mass spectrometry revealed that regioisomeric epoxy- and hydroxy-derivatives of EPA and AA are endogenous constituents of C. elegans. The endogenous EPA metabolite levels were increased by treating the worms with fenofibrate, which also induced the microsomal epoxygenase and hydroxylase activities. These results demonstrate for the first time that C. elegans shares with mammals the capacity to produce CYP-dependent eicosanoids and may thus facilitate future studies on the mechanisms of action of this important class of signaling molecules.
Keywords:Cytochrome P450, C. elegans, Polyunsaturated Fatty Acid, EPA, Eicosanoids, Cytochrome P450 Reductase, RNAi, High Performance Liquid Chromatography, Animals, Rats
Source:Archives of Biochemistry and Biophysics
Page Range:65-75
Date:1 April 2008
Official Publication:https://doi.org/10.1016/j.abb.2008.02.002
PubMed:View item in PubMed

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