Novel metabolic pathways for linoleic and arachidonic acid metabolism

Mehran F. Moghaddam, Kazuhiko Motoba, Babak Borhan, Franck Pinot, Bruce D. Hammock

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Mouse liver microsomes oxidized linoleic acid to form 9,10- or 12,13-epoxyoctadecenoate. These monoepoxides were subsequently hydrolyzed to their corresponding diols in the absence of the microsomal epoxide hydrolase inhibitor, 1,2-epoxy-3,3,3-trichloropropane. Furthermore, both 9,10- and 12,13-epoxyoctadecenoates were oxidized to diepoxyoctadecanoate at apparently identical rates by mouse liver microsomal P-450 epoxidation. Both epoxyoctdecenoates and diepoxyoctadecanoates were converted to tetrahydrofuran-diols by microsomes. Tetrahydroxides of linoleate were produced as minor metabolites. Arachidonic acid was metabolized to epoxyeicosatrienoates, dihydroxyeicosatrienoates, and monohydroxyeicosatetraenoates by the microsomes. Microsomes prepared from clofibrate (but not phenobarbital) -treated mice exhibited much higher production rates for epoxyeicosatrienoates and vic-dihydroxyeicosatrienoates. This indicated an induction of P-450 epoxygenase(s) and microsomal epoxide hydrolase in mice by clofibrate and not by phenobarbital. Incubation of synthetic epoxyeicosatrienoates with microsomes led to the production of diepoxyeicosadienoates. Among chemically generated diepoxyeicosadienoate isomers, three of them possessing adjacent diepoxides were hydrolyzed to their diol epoxides which cyclized to the corresponding tetrahydrofuran-diols by microsomes as well as soluble epoxide hydrolase at a much higher rate. Larger cyclic products from non-adjacent diepoxides were not observed. The results of our in vitro experiments suggest that linoleic and arachidonic acid can be metabolized to their tetrahydrofuran-diols by two consecutive microsomal cytochrome P-450 epoxidations followed by microsomal or soluble epoxide hydrolase catalyzed hydrolysis of the epoxides. incubation experiments with the S-9 fractions indicate that the soluble epoxide hydrolase is more important in this conversion. This manuscript is the first report of techniques for the separation and identification of regio and geometrical isomers of an interesting class of oxylipins and their metabolism by liver microsomes and S-9 fractions to THF-diols.

Original languageEnglish (US)
Pages (from-to)327-339
Number of pages13
JournalBiochimica et Biophysica Acta - General Subjects
Volume1290
Issue number3
DOIs
StatePublished - Aug 13 1996

    Fingerprint

Keywords

  • Cytochrome P-450
  • Epoxide
  • Hydrolase
  • Lipid
  • Oxylipin

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this