High impact information on CYP4F3

• To elucidate the role of CYP4F-mediated inactivation of LTB(4) in terminating the responses of PMN to LTB(4) and to identify a target for future genetic studies in mice, we have identified the enzyme that catalyzes the omega-1 and omega-2 oxidation of LTB(4) in mouse myeloid cells as CYP4F18 [1].
• Initially, we analyzed the distribution of CYP4F3 in human leukocytes and determined a lineage-specific pattern of isoform expression [2].
• We identified distinct transcriptional features in myeloid, lymphoid, and hepatic cells that indicate the presence of multiple promoters in the CYP4F3 gene [2].
• Alternative splicing determines the function of CYP4F3 by switching substrate specificity [3].
• We report that the use of alternate exons, each coding for 48 amino acids, generates isoforms of human CYP4F3 that differ in substrate specificity, tissue distribution, and biological function [3].

Biological context of CYP4F3

• The CYP4F3 gene contained 13 exons and spanned approximately 22.2 kb [4].
• The 5' flanking sequence downstream from -165 of the CYP4F2 gene has 75% similarity to the corresponding region of the CYP4F3 gene [5].
• Transcription start site of CYP4F3B mRNA in the leukocytes was identical to that of CYP4F3 mRNA [6].
• These results indicate that CYP4F12 has a different profile of substrate specificity from other CYP4F isoforms, enzymes responsible for metabolizing endogenous autacoids, therefore suggesting that it may play an important role in xenobiotic biotransformation in the human small intestine [7].
• Gene expression of a novel cytochrome P450 of the CYP4F subfamily in human seminal vesicles [8].

Anatomical context of CYP4F3

• CYP4F3 is the most tissue specific and most efficient LTB4 omega-hydroxylase, judging from its restricted localization in human polymorphonuclear leukocytes (PMN) and its very low Km value for LTB4 [9].
• Moreover, vicinal diol from both C18-epoxides and EETs were omega-hydroxylated by liver microsomes and by CYP4F2 and CYP4F3 [10].
• Promoter analysis of the CYP4F3 gene demonstrated that a region (-174/-90) of this gene was important for its promoter activity in the HL60 cells [6].
• CYP4F3 was expressed in one third of the peripheral monocytes, which omega-hydroxylated leukotriene B(4) (LTB(4)) at a rate 11 times lower than that of PMN [6].
• The cells that were differentiated into a form similar to monocytes/macrophages in shape by treatment with 12-myristate 13-acetate expressed mRNA for CYP4F3 and CYP4F3B [6].

Associations of CYP4F3 with chemical compounds

• In a preceding paper (Kikuta et al., 1993), we showed human polymorphonuclear leukocyte (PMN) LTB4 omega-hydroxylase to be a novel form of cytochrome P450, designated CYP4F3, on the basis of its cDNA cloning and expression in yeast cells [4].
• The HL60 cells, which were differentiated into PMN-like shapes by treatment with all-trans-retinoic acid (RA), also expressed CYP4F3, CYP4F3B and CYP4F12 [6].
• When expressed in Saccharomyces cerevisiae, the P450 catalyzes leukotriene B(4) omega-hydroxylation and arachidonic acid omega-hydroxylation, typical reactions of CYP4F isoforms [7].
• However, the inhibitory effects were only partial (about 20%) and thus it was thought that, although human CYP4F was involved in ebastine hydroxylation, another predominant enzyme exists [11].
• In this study, we have determined the activities of all of the rat and human CYP4A enzymes and two of the rat CYP4F enzymes, with respect to the omega-hydroxylation of phytanic acid [12].

Other interactions of CYP4F3

• The deduced protein showed 81.2 and 76.7% amino acid identity with the human enzymes CYP4F2 and CYP4F3 [8].
• This cDNA contains an entire coding region of a 524-amino-acid protein that is 81.7, 78.3, and 78.2% identical to CYP4F2, CYP4F3, and CYP4F8, respectively [7].
• A cDNA encoding a novel human CYP4F enzyme (designated CYP4F12) was cloned by PCR from a human small intestine cDNA library [7].
• In addition, treatment of CYP4B1, CYP4F3, and CYP4A5/7 with strong base generated a new, chromatographically distinct, polar heme species with a mass of 632.3 amu rather than 616.2 amu [13].
• We previously reported the cDNA cloning of a new CYP4F isoform, CYP4F11 [14].

Analytical, diagnostic and therapeutic context of CYP4F3

• Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization [4].
• Fluorescence in situ hybridization demonstrated that the CYP4F3 gene is located at 19p13.2 [4].
• Enzymatic activity assay, immunocytochemical staining, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of human leukocytes showed that polymorphonuclear leukocytes (PMNs) expressed CYP4F3B and CYP4F12 in addition to CYP4F3 [6].
• In the present study, we have used a combination of HPLC, LC/ESI-MS, and SDS-PAGE techniques to demonstrate that members of the mammalian CYP4B, CYP4F, and CYP4A subfamilies bind their heme in an unusually tight manner [13].
• Western blot analysis using a CYP4F polyclonal antibody also shows a considerably higher protein expression in female liver, kidneys, and lungs when compared with male rats [15].

References