arachidonate pathways

Arachidonic Acid (AA) is a 20-carbon polyunsaturated fatty acid (PUFA) found in the human body, widely present in the cell membranes of mammals, and is crucial for maintaining the fluidity and function of cell membranes. When cells are stimulated by inflammation or injury, phospholipase A2 (PLA2) is activated, hydrolyzing membrane phospholipids to produce free AA. After that, AA is transformed into various bioactive substances through three main metabolic pathways: the cyclooxygenase pathway (COX), the lipoxygenase pathway (LOX), and the cytochrome P450 pathway (CYP450). These metabolic products play key roles in physiological processes such as inflammatory responses, pain perception, and vasodilation.

COX pathway

The COX pathway is primarily composed of prostaglandin synthases, consisting of two isoenzymes, COX-1 and COX-2, which serve as the upstream core enzymes to convert AA into prostaglandin H2 (PGH2). PGH2 is subsequently transformed into other prostaglandins and thromboxanes through downstream enzymes.

The main distinction between the two enzymes lies in that COX-1 is constitutively expressed, whereas COX-2 is typically expressed in response to cytokines (such as IL-1 and TNF-α) and has a relatively short half-life. The expression preferences of COX pathway-related enzymes vary among different cell types; for example, mast cells predominantly produce prostaglandin D2 (PGD2), which is involved in inducing allergic responses, while macrophages produce thromboxane A2 (TXA2) among others, promoting platelet aggregation and vasoconstriction during tissue injury.

LOX pathway

Enzymes in the LOX pathway are mainly named according to the site of oxidation of AA, among which the most studied is 5-LOX, which adds an oxidative group at the fifth carbon atom. 5-LOX converts AA to leukotriene A4 (LTA4) through a two-step reaction involving the intermediate product 5-hydroperoxyeicosatetraenoic acid (5-HPETE). LTA4 is further converted to leukotriene B4 (LTB4) by LTA4 hydrolase, which acts as a chemotactic factor recruiting neutrophils and promoting the inflammatory response. LTA4 can also be converted to leukotriene C4 (LTC4) by LTC4 synthase, and further transformed into leukotriene D4 (LTD4) by gamma-glutamyl transferase; they belong to cysteinyl leukotrienes (CysLTs) and may cause bronchoconstriction, participating in asthma responses.

In addition to LTs, the LOX pathway may also produce lipoxins (LXs). After LTA4 is produced in neutrophils through 5-LOX, it may transfer to platelets, where it is converted into lipoxin A4 (LXA4) and lipoxin B4 (LXB4) through 12-LOX. LX acts as an anti-inflammatory factor, mediating the resolution of inflammation.

CYP450 pathway

The genes of the CYP pathway are predominantly expressed in hepatocytes, cardiomyocytes, vascular endothelial cells, and other cell types. It represents a large family, with the main subtypes including CYP2C and CYP2J. These genes primarily encode two types of enzymes, namely ω-hydroxylase and epoxygenase. The ω-hydroxylase metabolizes AA into hydroxyeicosatetraenoic acids (HETE), playing a role in the regulation of vascular functions, cell proliferation, and other processes; whereas, epoxygenase converts AA into epoxyeicosatrienoic acids (EET), with bioactive EET produced in the liver. EET can induce vasodilation, regulate cancer cell progression, promote the differentiation, proliferation, and migration of progenitor cells, and additionally influence capillary formation, inflammation, and endothelial cell apoptosis.