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

Abstract

Human CYP450 v-hydroxylases of the CYP4 family are known to convert arachidonic acid (AA) to its metabolite . 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 v-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 v-hydroxylation of PUFAs, whereas it was the (v-1)-hydroxylation with CYP1A1, CYP2C19, and CYP2E1. Finally, we demonstrated that the v9 and v3 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 v3 FAs could partly result from a shift in the generation of active hydroxylated metabolites of AA through a CYP-mediated catalysis.-Fer, M., L. Corcos, Y. Dréano, E. Plée-Gautier, J-P. Salaün, F. Berthou, and Y. Amet. Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism. J. Lipid Res. 2008Res. . 49: 2379Res. -2389

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…2). CYP4 family members are known to be involved in omega-hydroxylation of fatty acids, for example, human hepatic CYP4F3B is involved in omega oxidation of arachidonic acid to vasoactive 20-HETE (20-hydroxyeicosatetraenoic acid) [86]. 20-HETE is glucuronidated by several PPARα-induced UGTs, mainly by UGT2B7 [87].…”

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

“…Chromatography was done under gradient conditions with acetonitrile/0.1% formic acid in water as mobile phase. Gradient was started at 5% acetonitrile, fi sh oil n-3 PUFAs such as EPA (20:5 n-3) and DHA (22:6 n-3) (18)(19)(20)(21)(22). CYP2C and CYP2J isoforms convert AA to EETs, EPA to epoxyeicosatetraenoic acids (EEQs), and DHA to epoxydocosapentaenoic acids (EDPs).…”

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

“…Among P450s, including CYP4A11, CYP4F2, and CYP4F3A/3B, the latter is the best known to -hydroxylate the essential FA arachidonate to 20-HETE, a potent vasoactive ecosanoid and anti-inflammatory agent (Kalsotra and Strobel, 2006;Fer et al, 2008). The CYP4Fs are predominantly expressed in liver and kidney, although CYP4F3A is found in myeloid tissue.…”