Human cytochrome P450 4F3: structure, functions, and prospects

Abstract

Cytochrome P450 4F3 (CYP4F3), originally identified as one of the leukotriene B4 ω-hydroxylases, belongs to a CYP gene family that comprises several members, which participate in the metabolism of various endobiotics, as well as some xenobiotics. The CYP4F gene family is clustered in a 0.5-Mb stretch of genomic DNA on the p13 region of chromosome 19. Apart from the ω-hydroxylation of leukotriene B4 and prostaglandins, CYP4F3 is the main catalyst in the oxidation of fatty acid epoxides. CYP4F3 expression results from the synthesis of two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single pre-mRNA precursor molecule. Remarkably, the selection of either isoform is part of a tissue-specific control through which CYP3F3A is mostly expressed in leukocytes and CYP4F3B mostly in the liver. Recently, CYP4F3 single nucleotide polymorphisms have been incriminated in the onset of pathologies, including celiac or Crohn's diseases. Although much has been discovered in the regulation and function of CYP4F2, the closest CYP4F subfamily member, analyses of CYP4F3 enzymes lag somewhat behind in the field of our knowledge. In this short review, emphasis will be placed on the regulation and the functional roles of human CYP4F3.

Genetic Polymorphisms in Fatty Acid Metabolism Modify the Association Between Dietary n3

“…In particular, leukotriene B4 (LTB4) has strong pro-inflammatory effects and is present in higher concentration in tissues at the site of inflammation accompanied by an increase in expression of enzymes responsible for its biosynthesis 16, 50-53 . CYP4F3 is an enzyme belonging to the cytochrome P450 superfamily, encoded by a gene CYP4F3 on chromosome 19 22, 41, 54 . This forms the precursor for two enzyme subfamilies, CYP4F3A and CYP4F3B which localize to leukocytes and the liver respectively.…”

Role of Cytochrome P450s in Inflammation

“…Enzymes with capability of converting arachidonic acid to 20-HETE in vitro include CYP4F2 and CYP4F3B (Harmon et al, 2006;Lasker et al, 2000). Transgenic mouse models that express human CYP4F2 increase bioactive 20-HETE production in vivo (Cheng et al, 2014;Liu et al, 2009), and sequence variants in CYP4F2 and CYP4A11 are associated Kalsotra and Strobel (2006) and Corcos et al (2012) for references. c Association between disease risk and genetic polymorphisms is strongest for CYP4F22 and CYP4V2 genes (Kelly, Nakano, Rohatgi, Yarov-Yarovoy, & Rettie, 2011), but more controversial for CYP4A11, CYP4F2, and CYP4F3 genes (references in text).…”

Pathway‐analysis of published genome‐wide association studies of lung cancer: A potential role for the CYP4F3 locus

“…| 1667 anti-inflammatory leukotrienes (ie, LTB4) indicates that they may function in both the activation and resolution phases of the inflammatory response. 42 The CYP4F3 rs4646904 G>A variant was a novel, potentially functional SNP that had the smallest P value in the present meta-analysis of the TRICL GWASs. Although CYP4F3 rs4646904 G>A is a synonymous variant, it is located within an exon splicing enhancer (ESE), 25 which has discrete sequences within exons that promote both constitutive and regulated splicing.…”

“…Human CYP4F3s are the main catalysts in the oxidation of FAs: they can ω‐hydroxylate a variety of long chains and very long chains as well as saturated, unsaturated, and branched chain FAs, vitamins with long alkyl side chains, and the physiologically important prostaglandins and hydroeicosatetraenoic acids . Additionally, the ability of CYP4F3 to ω‐hydroxylate both pro‐ and anti‐inflammatory leukotrienes (ie, LTB4) indicates that they may function in both the activation and resolution phases of the inflammatory response . The CYP4F3 rs4646904 G>A variant was a novel, potentially functional SNP that had the smallest P value in the present meta‐analysis of the TRICL GWASs.…”