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

Human CYP450 v -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 docosahex- aenoic acid (DHA) by either human recombinant CYP4s en- zymes or human liver microsomal preparations. CYP4F3A and CYP4F3B were the most efficient v-hydroxylases of these PUFAs. Moreover, the differences in the number of unsatura- tions 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 v 9a ndv 3P UFAs (ETA, EPA, and DHA) could all be used as alternative sub- strates 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 metabo- lites of AA through a CYP-mediated catalysis.— Fer, M., L. Corcos, Y. Dreano, E. Plee-Gautier, J-P. Salaun, 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. 2008. 49: 2379-2389.