Aspirin Intolerance: Experimental Models for Bed-to-Bench

Yamashita, Masamichi

As shown in Fig. (2) , the enzyme phospholipase A 2 releases fatty acids from cell membrane phospholipids. Arachidonic acid is one of the fatty acids released and it is metabolized into various substances, including prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs), which are thought to make a major contribution to the pathogenesis of inflammatory diseases. PGD 2 and PGE 2 are arachidonic acid metabolites produced by cyclooxygenase (COX, also called prostaglandin G/H synthase, PGHS, EC 1.14.99.1) which metabolizes ara-chidonic acid to PGG 2 by its cyclooxygenase activity and then metabolizes PGG 2 to PGH 2 by its hydroperoxidase activity (Fig. 2) . Metabolites of COX are known to contribute to inflammation. In 1990s, two subtypes of the COX enzyme were found. One of these was named COX-1 and was found to be constitutively expressed by cells. The other was named COX-2 [21, 22] , and this was found to be induced by physiological and experimental inflammatory stimuli, such as the carcinogenic promoter 12-O-tetradecanoylphorbol 13acetate thapsigargin, or calcium ionophore A23187 [23] [24] [25] [26] . Transcription of COX-2 protein is controlled by various transcription factors, including nuclear factor-κB (NF-κB) and AP-1 [27] [28] [29] [30] [31] , via degradation of the inhibitory protein, IκB [32] . Specific COX-2 inhibitors were developed to avoid the side effect of gastrointestinal ulceration, and it was revealed that selectivity is due to difference of tertiary protein structure between COX-1 and COX-2 [33] [34] [35] [36] .