The Functions of Cytochrome P450 ω-hydroxylases and the Associated Eicosanoids in Inflammation-Related Diseases

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.

Role of Inflammatory Processes in Hemorrhagic Stroke

“…157,158,[160][161][162][163] In particular, 20-hydroxyeicosatetraenoate has been shown to activate nuclear NF-κB, increase adhesion molecules, stimulate the production of inflammatory cytokines in endothelial cells, and promote vascular inflammation. 164 Both epoxyeicosatrienoates and hydroxyeicosatetraenoates have been implicated in SAH and explored as potential therapeutic targets. The level of 20-hydroxyeicosatetraenoates is increased in the CSF of humans and animals after SAH, which correlates with poor outcomes, and inhibitors of 20-hydroxyeicosatetraenoate synthesis prevent the acute and delayed changes in cerebral blood flow in experimental SAH.…”

Kurarinone alleviated Parkinson's disease via stabilization of epoxyeicosatrienoic acids in animal model

“…Therefore, in this study, we first tested the ability of kurarinone to reduce neuroinflammation and improve behavioral deficits in a PD mice model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To understand how kurarinone decreases inflammation and because its treatment resulted in elevated levels of epoxyeicosatrienoic acids (EETs), endogenous signaling molecules that control inflammation ( 27 ), we used several biochemical methods to determine the molecular target of kurarinone. The interactions between kurarinone and soluble epoxide hydrolase, the main enzyme metabolizing EETs ( 28 ), were confirmed using enzyme kinetics and cocrystallization.…”

A novel mutation of CYP4V2 gene associated with Bietti crystalline dystrophy complicated by choroidal neovascularization

“…Zhang et al [16] have demonstrated that PUFA played an important role in mitochondrial damage inducing RPE degeneration in BCD patients and suggested that adeno-associated virus 2 (AAV2)-mediated gene therapy may be used as the treatment of BCD. Furthermore, some FA metabolites are involved in anti-inflammation, immunoregulation and so on, so that the defections of CYP4V2 protein function may influence the signaling pathway and even influence other aspects [17][18] . Therefore, the mutations of the CYP4V2 gene may have broad influences, and we still need more detailed studies to clarify the mechanism of BCD.…”