Transcellular biosynthesis of eicosanoids

Abstract

The metabolism of arachidonic acid into biologically active compounds involves the sequential activity of a number of enzymes, sometimes showing a unique expression profile in different cells. The main metabolic pathways, namely the cyclooxygenases and the 5-lipoxygenase, both generate chemically unstable intermediates: prostaglandin (PG) H2 and leukotriene (LT) A4, respectively. These are transformed by secondary enzymes into a variety of chemical structures known collectively as the lipid mediators. Although some cells express all the enzymes necessary for the production of biologically active compounds, it has been shown that eicosanoids are often the result of cell-cell interactions involving the transfer of biosynthetic intermediates, such as the chemically reactive PGH2 and leukotriene LTA4, between cells. This process has been defined as the transcellular pathway of eicosanoid biosynthesis and requires both a donor cell to synthesize and release one component of the biosynthetic cascade and an accessory cell to take up that intermediate and process it into the final biologically active product. This review will summarize the evidence for transcellular biosynthetic events, occurring in isolated cell preparations, complex isolated organ systems, and in vivo, that result in the production of prostaglandins, leukotrienes, and lipoxins.

Botanical oils enriched in n-6 and n-3 FADS2 products are equally effective in preventing atherosclerosis and fatty liver

“…BO, which is enriched in GLA, was as atheroprotective as EO and FO despite its signifi cant enrichment of RBCs and plasma and liver lipid fractions with AA, a fatty acid precursor to pro-infl ammatory leukotrienes and prostaglandins ( 42 ). Concerns that elevated membrane AA may result in increased cellular infl ammation that exacerbates atherosclerosis lack support in human studies ( 13 ).…”

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

“…LTB 4 levels are elevated in adipose tissue during obesity (11)(12)(13), and LTB 4 has been described to play a role in the development of insulin resistance and to directly decrease insulin signaling in myocytes and hepatocytes in vitro (5,14,15). In addition, although the activation of the ALOX5/ALOX5AP complex is key to leukotriene synthesis, it can alternatively lead to the biosynthesis of other compounds, such as lipoxins (16). The intermediate LTA 4 can be converted to lipoxin A4 (LXA 4 ) (5S, 6R, 15S-trihydroxy-eicosa-7E, 9E, 11Z, 13E-tetraenoic acid) by action of 12-lipoxygenase (ALOX12) in humans (17,18) or in mice by arachidonate 15-lipoxygenase (ALOX15 or ALOX12/15) (19,20).…”

Target Identification and Validation of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate, an Anti-Inflammatory Natural Product

“…Subsequently, human whole blood was used because it is a more reliable evaluation system, as it is composed of erythrocytes, platelets and various leukocytes. This mimics the in vivo microenvironment and can be used as a good transcellular metabolic system for drug evaluation (31). There is accumulating evidence supporting the significance of the transcellular biosynthetic pathway of eicosanoids in inflammation (30)(31).…”

“…This mimics the in vivo microenvironment and can be used as a good transcellular metabolic system for drug evaluation (31). There is accumulating evidence supporting the significance of the transcellular biosynthetic pathway of eicosanoids in inflammation (30)(31). The identification of 5-LOX as the target of HOEC was extensively validated by data from pure enzyme assays, single cell systems and transcellular systems, and HOEC was proven to be a potent and specific 5-LOX inhibitor in vitro and ex vivo.…”