Abstract
The cytochrome P450 (CYP) ω-hydroxylases are a subfamily of CYP enzymes. While CYPs are the main metabolic enzymes that mediate the oxidation reactions of many endogenous and exogenous compounds in the human body, CYP ω-hydroxylases mediate the metabolism of multiple fatty acids and their metabolites via the addition of a hydroxyl group to the ω- or (ω-1)-C atom of the substrates. The substrates of CYP ω-hydroxylases include but not limited to arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, epoxyeicosatrienoic acids, leukotrienes, and prostaglandins. The CYP ω-hydroxylases-mediated metabolites, such as 20-hyroxyleicosatrienoic acid (20-HETE), 19-HETE, 20-hydroxyl leukotriene B4 (20-OH-LTB4), and many ω-hydroxylated prostaglandins, have pleiotropic effects in inflammation and many inflammation-associated diseases. Here we reviewed the classification, tissue distribution of CYP ω-hydroxylases and the role of their hydroxylated metabolites in inflammation-associated diseases. We described up-regulation of CYP ω-hydroxylases may be a pathogenic mechanism of many inflammation-associated diseases and thus CYP ω-hydroxylases may be a therapeutic target for these diseases. CYP ω-hydroxylases-mediated eicosanods play important roles in inflammation as pro-inflammatory or anti-inflammatory mediators, participating in the process stimulated by cytokines and/or the process stimulating the production of multiple cytokines. However, most previous studies focused on 20-HETE,and further studies are needed for the function and mechanisms of other CYP ω-hydroxylases-mediated eicosanoids. We believe that our studies of CYP ω-hydroxylases and their associated eicosanoids will advance the translational and clinal use of CYP ω-hydroxylases inhibitors and activators in many diseases.
Highlights
Cytochrome P450 (CYP) enzymes, discovered in the early 1960s, are a superfamily of heme containing membrane bound monoxygenases which is available in microorganisms, plants, animals, and humans (Guengerich et al, 2016; Elfaki et al, 2018)
CYP4F3B is mainly expressed in the human liver and kidney, but not in myeloid cells, which is more active in the hydroxylation of arachidonic acid (AA) and other ω-3 polyunsaturated fatty acids (PUFA) than in hydroxylating leukotriene B4 (LTB4) (Fer et al, 2008)
20-hyroxyleicosatrienoic acid (20-HETE) is the major metabolite of arachidonic acid mediated by cytochrome P450 (CYP) ω-hydroxylase, which plays an important role in the regulation of cardiovascular disease, renal function disorder, carcinogenic condition, and other inflammatory diseases
Summary
Cytochrome P450 (CYP) enzymes, discovered in the early 1960s, are a superfamily of heme containing membrane bound monoxygenases which is available in microorganisms, plants, animals, and humans (Guengerich et al, 2016; Elfaki et al, 2018). This article reviews the activity and expression changes of CYP ω-hydroxylase in inflammationrelated diseases, and the enzyme-mediated metabolites, such as 20-HETE, which trigger the downstream signaling pathway and induce more pathological changes. The human CYP enzymes that catalyze ω-hydroxylation of fatty acids include CYP4A, CYP4B, CYP4F, and CYP2U1 (Chuang et al, 2004; Hardwick, 2008) (Table1).
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