Index
The screening of COX route research is essential to understanding COX deficiency, and it is advantageous to examine the variable effects of inhibition.
Regardless of the etiology, a deficiency of cyclooxygenase (COX), a key regulatory enzyme in the synthetic pathway of eicosanoid production, results in beneficial and harmful physiological conditions about the imbalances of eicosanoids.
Eicosanoids, including prostaglandins, leukotrienes, thromboxanes, and lipoxins, are responsible for multiple inflammatory, mitogenic, and angiogenic activities in various tissue and organ systems.
Therefore, cyclooxygenase, also known as prostaglandin-endoperoxide synthase (PTGS), COX of fatty acids, prostaglandin H (PGH) synthase, and EC 1.14.99.1 is involved in the production of fever, inflammation, and pain.
History
In 1930, American gynecologists Kurzok and Lieb first described seminal fluid’s stimulatory effects on human uterine muscle tissue.
A few years later, von Euler of Sweden independently discovered similar effects of seminal human fluid on smooth muscle tissue. He located the biological activity in a fraction of fat-soluble acids he called “prostaglandin,” hypothesizing that these substances originate in the prostate gland.
Two decades later, prostaglandins were deduced as a family of related compounds containing 20-carbon polyunsaturated fatty acids with a cyclopentane ring, as depicted below:
- Twenty carbon polyunsaturated fatty acids with cyclone.
- Twenty carbon polyunsaturated fatty acids with cyclopentane ring.
In 1964, after recognizing this basic structure, Bergstrom and his colleagues successfully synthesized the series two prostaglandins from arachidonic acid using seminal sheep fluid.
However, the physiological importance of prostaglandin production did not develop until 1971, when Vane, Smith, and Willis discovered that aspirin and indomethacin inhibited the biosynthesis of prostaglandins.
Additional research by Smith concluded that aspirin and indomethacin inhibited synthesis by explicitly blocking the oxygenation of arachidonic acid.
These historical discoveries collected information about the cyclooxygenase pathway of arachidonate metabolism.
Etiology
Cyclooxygenase deficiency typically denotes an acquired cause-and-effect relationship between the enzyme activity of the protein and the nonsteroidal anti-inflammatory drugs (NSAIDs).
However, while studying bleeding families in the Aland Islands, Nyman and co-investigators reported an autosomal dominant inheritance pattern for cyclooxygenase deficiency.
In addition, Hello and his colleagues described three members of the family of 2 successive generations with bleeding tendencies and concluded that their platelets were compatible with a cyclooxygenase deficiency.
This study also described an autosomal dominant inheritance pattern but deduced that COX was not essential for the aggregation and release of adenosine triphosphate (ATP) against high concentrations of collagen.
The documented hemorrhagic constitutional and family disorders have been associated with the deficiency of platelet COX-1.
Pathophysiology in cyclooxygenase deficiency
Two types of platelet COX-1 deficiency have been recognized. The type 1 defect is characterized by a complete absence of COX-1 protein in platelets. In type 2 deficiency, on the other hand, there is an average level of protein, but the enzymatic activity of COX-1 is altered.
However, the physiological consequences of cyclooxygenase deficiency are best described as acquired rather than inherited disorders.
The effect of COX-1 deficiency varies from one tissue to another and is primarily determined by the fate of the final products.
Several studies have concluded that the direct inhibition of COX-1 coincides with a loss of cytoprotection. COX-1 deficiency has been considered a significant participant in gastric and renal pathology.
However, Langenbach and his colleagues reported that mice deficient in COX-1 live without incident despite a 99% reduction in overall prostaglandin production.
He also emphasized a lack of gastric and renal pathology despite the observed deficiency of prostaglandins. Confirming the previous literature, Langenbach reported that female mice deficient in COX-1 had difficulties with childbirth while male mice deficient in COX-1 were unaffected.
Contrary to popular belief, Langenbach has also shown that COX-1 deficiency correlates with reduced edema versus inflammatory mediators that increase arachidonate, which illuminates its importance in the inflammatory cascade.
Without significant controversy, the consensus has been that the inhibition of COX-2 is responsible, in part, for the antipyretic, analgesic, and anti-inflammatory properties of NSAIDs.
However, novel research using genetically altered COX knockout mice has discovered new ramifications associated with COX-2.
First, Lim and colleagues observed that female mice deficient in COX-2 incurred reproductive failures through ovulation abnormalities and fertilization.
