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Papers In Press, published online ahead of print August 1, 2004
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Journal of Lipid Research, Vol. 45, 1446-1458, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology
* Laboratoire de Biochimie-Equipe d'Accueil 948, Université de Bretagne Occidentale, Faculté de Médecine, CS 93837, 29238 Brest Cédex 3, France
Unité Mixte de Recherche 7139 Centre National de la Recherche Scientifique/Goëmar/Université Pierre et Marie Curie, Station Biologique, 29682 Roscoff, France
1 To whom correspondence should be addressed. e-mail: jp.salaun{at}univ-brest.fr
CYP4F isoforms are involved in the oxidation of important cellular mediators such as leukotriene B4 (LTB4) and prostaglandins. The proinflammatory agent LTB4 and cytotoxic leukotoxins have been associated with several inflammatory diseases. We present evidence that the hydroxylation of Z 9(10)-epoxyoctadecanoic, Z 9(10)-epoxyoctadec-Z 12-enoic, and Z 12(13)-epoxyoctadec-Z 9-enoic acids and that of monoepoxides from arachidonic acid [epoxyeicosatrienoic acid (EET)] is important in the regulation of leukotoxin and EET activity. These three epoxidized derivatives from the C18 family (C18-epoxides) were converted to 18-hydroxy-C18-epoxides by human hepatic microsomes with apparent Km values of between 27.6 and 175 µM. Among recombinant P450 enzymes, CYP4F2 and CYP4F3B catalyzed mainly the 
-hydroxylation of C18-epoxides with an apparent Vmax of between 0.84 and 15.0 min–1, whereas the apparent Vmax displayed by CYP4F3A, the isoform found in leukocytes, ranged from 3.0 to 21.2 min–1. The rate of -hydroxylation by CYP4A11 was experimentally found to be between 0.3 and 2.7 min–1. CYP4F2 and CYP4F3 exhibited preferences for -hydroxylation of Z 8(9)-EET, whereas human liver microsomes preferred Z 11(12)-EET and, to a lesser extent, Z 8(9)-EET. Moreover, vicinal diol from both C18-epoxides and EETs were -hydroxylated by liver microsomes and by CYP4F2 and CYP4F3.
These data support the hypothesis that the human CYP4F subfamily is involved in the -hydroxylation of fatty acid epoxides. These findings demonstrate that another pathway besides conversion to vicinal diol or chain shortening by ß-oxidation exists for fatty acid epoxide inactivation.
Abbreviations: AA, arachidonic acid; BSTFA, N,O-bistrimethylsilyltrifluoroacetamide; C18-epoxides, epoxidized derivatives from the C18 family; DHET, dihydroxyeicosatrienoic acid; DiOME, dihydroxyC18:1 acid (vicinal diol); DiSTA, dihydroxystearic acid (vicinal diol); EET, epoxyeicosatrienoic acid; EH, epoxide hydrolase; HEET, hydroxyepoxyeicosatrienoic acid; HEpOME, hydroxyepoxyoctadecanoic acid; HEpSTA, hydroxy-9(10)-epoxyoctadecanoic acid; HETE, hydroxyeicosatetraenoic acid; LC-MS, liquid chromatography-mass spectrometry; LTB4, leukotriene B4; Me/TMS, methyl ester trimethylsilyl ether; PPAR
, peroxisome proliferator-activated receptor ; RP, reversed-phase; Rt, retention time; TMCS, trimethylchlorosilane; TriHET, trihydroxyeicosatrienoic acid; TriSTA, trihydroxystearic acid (triol); Z 9(10)-EpOME, Z 9(10)-epoxyoctadec-Z 12-enoic acid; Z 12(13)-EpOME, Z 12(13)-epoxyoctadec-Z 9-enoic acid; Z 9(10)-EpSTA, Z 9(10)-epoxyoctadecanoic acid (epoxystearic acid)
Supplementary key words leukotoxin • epoxyeicosatrienoic acid • cytochrome P450 • oxylipin • liver • microsomes • recombinant cytochrome P450 • hydroxylation
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