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Journal of Lipid Research, Vol. 49, 2379-2389, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism¹

Maude Fer^*, Laurent Corcos^*,, Yvonne Dréano^*, Emmanuelle Plée-Gautier^*, Jean-Pierre Salaün^*,, François Berthou^* and Yolande Amet^2,*

^* Laboratoire de Biochimie EA 948, Faculté de Médecine, Université de Bretagne Occidentale, Brest, France
Institut National de la Santé et de la Recherche Médicale U613, Faculté de Médecine, Université de Bretagne Occidentale, Brest, France
Centre National de la Recherche Scientifique UMR 7139, Station Biologique, Roscoff, France

¹ CYPs, enzymes belonging to the cytochromes P450 families, are designated here from the nomenclature available on Dr. David Nelson's website for cytochrome P450s (http://drnelson.utmem.edu/human.P450.table.html).

Published, JLR Papers in Press, June 24, 2008.

M.F. was supported by a fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche.

² To whom correspondence should be addressed. e-mail: yolande.amet{at}univ-brest.fr

Human CYP450 -hydroxylases of the CYP4 family are known to convert arachidonic acid (AA) to its metabolite 20-hydroxyeicosatetraenoic acid (20-HETE). This study deals with hydroxylations of four PUFAs, eicosatrienoic acid (ETA), AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) by either human recombinant CYP4s enzymes or human liver microsomal preparations. CYP4F3A and CYP4F3B were the most efficient -hydroxylases of these PUFAs. Moreover, the differences in the number of unsaturations of ETA, AA, and EPA allowed us to demonstrate a rise in the metabolic rate of hydroxylation when the double bond in 14-15 or 17-18 was missing. With the CYP4F enzymes, the main pathway was always the -hydroxylation of PUFAs, whereas it was the (-1)-hydroxylation with CYP1A1, CYP2C19, and CYP2E1. Finally, we demonstrated that the 9 and 3 PUFAs (ETA, EPA, and DHA) could all be used as alternative substrates in AA metabolism by human CYP4F2 and -4F3B. Thus, they decreased the ability of these enzymes to convert AA to 20-HETE. However, although ETA was the most hydroxylated substrate, EPA and DHA were the most potent inhibitors of the conversion of AA to 20-HETE. These findings suggest that some physiological effects of 3 FAs could partly result from a shift in the generation of active hydroxylated metabolites of AA through a CYP-mediated catalysis.

Supplementary key words -hydroxylation • (-1)-hydroxylation • inhibition

Abbreviations: AA, arachidonic acid; APCI, atmospheric pressure chemical ionization; DBA, n-dibutylamine; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ETA, eicosatrienoic acid; HETE, hydroxyeicosatetraenoic acid; LTB4, leukotriene B4; VLCFA, very long-chain FA

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