Enthusiastically exploring various aspects of salicylate sensitivity, one topic I stumble upon frequently is how exactly dietary-induced salicylate reactions occur. A few blog articles mention the involvement of the COX-1 enzyme; its inhibition can apparently lead to undesired symptoms. With my interest piqued, I conducted a little research into COX-1 enzymes, in particular, their relation to aspirin, a drug derived from salicylic acid. More of a clarification than a revelation, what I learned was that presently there isn’t any scientific literature pertaining to dietary salicylates having a direct role in COX-1 inhibition, and therefore, it’s not believed to be the mechanism by which salicylate-sensitivity reactions occur.

In conditions such as aspirin intolerance or Aspirin Exacerbated Respiratory Disease (a chronic inflammatory disorder of the sinuses and lungs), reactions have been explained by the irreversible inhibition of the COX-1 enzyme (1)(2)(3).

Since the chemical name for aspirin is acetylsalicylate, it’s easy to see why people mistakenly assume that limiting salicylates in the diet, along with the drug itself, will help ward off symptoms in patients of aspirin intolerance and AERD. However, it’s not actually salicylates that inhibit the COX-1 enzyme, rather it’s the acetyl part of the compound that plays the inhibitory role (4). 

In our body, we have two main enzyme pathways that act on arachidonic acid; a molecule involved in the synthesis of inflammatory mediators such as prostaglandins and leukotrienes. The cyclooxygenase (COX-1) pathway leads to the production of prostaglandins and the lipoxygenase pathway leads to the production of leukotrienes. Both prostaglandins and leukotrienes play an important role in the inflammatory response, leading to pain (the prostaglandins) and symptoms associated with conditions such as asthma and eczema (the leukotrienes) (6)(7). 

Specifically, aspirin acts by preventing the formation of prostaglandins. The drug does this by taking the acetyl group off the salicylic acid and putting it on the COX-1 enzyme, blocking it. While effective for pain, inhibition of the COX-1 enzyme also leads to a build-up of arachidonic acid. Excess arachidonic acid is now funneled into the lipoxygenase pathway leading to increased production of leukotrienes. AERD patients have an impaired COX pathway which results in an acute reaction when they take aspirin. Symptoms of the condition may be explained by the more dramatic surge of leukotrienes than normal that they experience, however, this being caused by the “shunting” of arachidonic acid into the lipoxygenase pathway is just a hypothesis and the actual relationship between the COX pathways, leukotriene levels and aspirin sensitivity remain unclear (8)(9).

As salicylates are non-acetylated, they don’t have the same effect in inhibiting the COX-1 enzyme as aspirin and thus may not be a factor in symptoms associated with AERD or aspirin allergy. It also explains why the mechanism behind salicylate intolerance likely isn’t the direct inhibition of the COX-1 enzyme by dietary salicylates.

That being said, it’s been postulated that salicylic acid could be playing a role in reactions experienced by some people who are sensitive to acetylsalicylic acid (4)(5), there just aren’t any carefully controlled studies yet which support the claim.

Unfortunately, the biological mechanisms responsible for hypersensitivity to food-derived salicylates are poorly understood. While dietary salicylates have not been found to inhibit the COX-1 enzyme, it’s hoped that with further research into the salicylate content of foods and the metabolic processes involved in salicylate breakdown, a greater understanding of the condition will be achieved.

Brigid xx

References

(1) Schäfer, Dirk, and Steffen Maune. “Pathogenic Mechanisms and In Vitro Diagnosis of AERD.” Journal of allergy vol. 2012 (2012): 789232. doi:10.1155/2012/789232

(2) Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004 Sep;56(3):387-437. doi: 10.1124/pr.56.3.3. PMID: 15317910.

(3) Fuster V, Sweeny JM. Aspirin: a historical and contemporary therapeutic overview. Circulation. 2011 Feb 22;123(7):768-78. doi: 10.1161/CIRCULATIONAHA.110.963843. PMID: 21343593.

(4) Hare, L. G., Woodside, J. V., & Young, I. S. (2003). Dietary salicylates. Journal of clinical pathology , 56 (9), 649–650. https://doi.org/10.1136/jcp.56.9.649

(5) Kęszycka, Paulina K et al. “Effectiveness of Personalized Low Salicylate Diet in the Management of Salicylates Hypersensitive Patients: Interventional Study.” Nutrients vol. 13,3 991. 19 Mar. 2021, doi:10.3390/nu13030991

(6) Hallstrand, Teal S, and William R Henderson Jr. “An update on the role of leukotrienes in asthma.” Current opinion in allergy and clinical immunology vol. 10,1 (2010): 60-6. doi:10.1097/ACI.0b013e32833489c3

(7) Ruzicka T. Leukotrienes in atopic eczema. Acta Derm Venereol Suppl (Stockh). 1989;144:48-49.

(8) Gray, P A et al. “Effects of non-steroidal anti-inflammatory drugs on cyclo-oxygenase and lipoxygenase activity in whole blood from aspirin-sensitive asthmatics vs healthy donors.” British journal of pharmacology vol. 137,7 (2002): 1031-8. doi:10.1038/sj.bjp.0704927

(9) Knapp HR, Sladek K, Fitzgerald GA. Increased excretion of leukotriene E4 during aspirin-induced asthma. J Lab Clin Med. 1992 Jan;119(1):48-51. PMID: 1309376.