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Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer.

ABSTRACT: Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosanoids, such as epoxyeicosatrienoic acids (EETs), epoxyoctadecenoic acids (EpOMEs), epoxyeicosatetraenoic acids (EpETEs), and epoxydocosapentaenoic acids (EDPs), as well as hydroxyeicosatetraenoic acids (HETEs), in tumorigenesis and cancer progression have not been fully elucidated yet. Here we summarized the association of polymorphisms of CYP monooxygenases with cancers and the pleiotropic functions of CYP monooxygenase-mediated eicosanoids (EETs, EpOMEs, EpETE, EDPs, and 20-HETE) in the tumorigenesis and metastasis of multiple cancers, including but not limited to colon, liver, kidney, breast and prostate cancers, which hopefully provides valuable insights into cancer therapeutics. We believe that manipulation of CYPs with or without supplement of ?-3 PUFAs to regulate eicosanoid profile is a promising strategy to prevent and/or treat cancers.

SUBMITTER: Luo Y

PROVIDER: S-EPMC7658919 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer.

Luo Ying Y Liu Jun-Yan JY

Frontiers in pharmacology 20201029

Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosan ...[more]

PMID: 33192522

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Project description:OBJECTIVE:Accumulating preclinical and epidemiologic evidence has emerged to suggest that modulation of cytochrome P450 (CYP)-mediated eicosanoid metabolism may be a viable vascular protective therapeutic strategy for the secondary prevention of coronary artery disease (CAD). The functional relationship between CYP-derived eicosanoid metabolite levels and vascular dysfunction in humans with established CAD, however, has not been evaluated. Therefore, we characterized the relationship between inter-individual variation in soluble epoxide hydrolase (sEH) and CYP ?-hydroxylase metabolism and established vascular function phenotypes predictive of prognosis in a cohort of patients with atherosclerotic cardiovascular disease. METHODS:Plasma epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHET), and 20-hydroxyeicosatetraenoic acid (20-HETE) levels were quantified by HPLC-MS/MS in 106 patients with stable, angiographically-confirmed CAD. Relationships between biomarkers of CYP-mediated eicosanoid metabolism and vascular function phenotypes were evaluated by Pearson's correlation. RESULTS:A significant inverse association was observed between 20-HETE levels (a biomarker of CYP ?-hydroxylase metabolism) and brachial artery flow-mediated dilation (r = -0.255, p = 0.010). An inverse association was also observed between 14,15-EET:DHET ratios (a biomarker of sEH metabolism) and both monocyte chemoattractant protein-1 levels (r = -0.252, p = 0.009) and a consolidated cellular adhesion molecule 'score' reflecting the levels of E-selectin and P-selectin (r = -0.216, p = 0.027). No associations with C-reactive protein or epithelial neutrophil-activating protein-78 levels were observed. CONCLUSIONS:Collectively, these findings demonstrate that enhanced CYP ?-hydroxylase and sEH metabolic function are associated with more advanced endothelial dysfunction and vascular inflammation, respectively, in patients with established atherosclerotic cardiovascular disease. These findings lay the foundation for future clinical research in this area.

Dataset Information

Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer.

Publications

Pleiotropic Functions of Cytochrome P450 Monooxygenase-Derived Eicosanoids in Cancer.

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