COX-3): Filling in the Gaps Toward a COX Continuum?

Commentary

Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?

Timothy D. Warner*† and Jane A. Mitchell‡

*The William Harvey Research Institute, Bart’s and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom; and ‡National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6L, United Kingdom

umans have been using nonsteroid antiinflammatory effects of NSAIDs. model did not appear to explain every- Hantiinflammatory drugs (NSAIDs) in Similarly, prostanoids such as PGI2 and thing. Even though in inflammatory mod- various forms for more than 3,500 years PGE2 were found to be protective to the els COX-2 inhibitors were as active as (1). They are still our favorite medicines. stomach and so inhibition of their forma- traditional NSAIDs, worked similarly in Estimates vary, but it appears, for in- tion provided an explanation for the gas- both human and animal models of pain, stance, that each year we consume around trointestinal toxicity associated with and reduced fever in a similar way to the 40,000 metric tons of aspirin, equating to prolonged and high-dose use of NSAIDs NSAIDs (1, 5, 16), there were still some about 120 billion aspirin tablets (300 mg is (1, 5, 6). The inhibition of COX in plate- confusing issues. For example, the wide- a standard size). In addition, dozens of lets provided an explanation for the ability spread use of the newer generation of other NSAIDs and NSAID formulations of aspirin to reduce blood clotting (7). But COX-2-selective compounds demon- are available and enthusiastically con- still there were a number of questions that strated that COX-2 also had physiological sumed in most countries. However, de- remained unanswered through the 1970s roles, being involved, for instance, in the spite this long history and large volume of and 1980s. For instance, why, when used at maintenance of fluid balance by the kid- use, we still have an incomplete under- similar antiinflammatory doses, were the ney (17). The COX-1͞-2 model was also standing of how the NSAIDs achieve their NSAIDs differently toxic to the gastroin- not accommodating to the characteristics actions. Most recently, molecular biology, testinal tract (5, 8)? Also, how did acet- of acetaminophen: although its antipyretic together with pharmacology, has brought aminophen fit into this scheme? Did it act and analgesic effects might be explained the greatest steps forward in knowledge. It by inhibiting COX? Intriguingly, test tube by inhibition of COX-2, why was acet- is in this vein that Dan Simmon’s group experiments showed that acetaminophen aminophen not antiinflammatory (18)? report the discovery of a novel cyclooxy- might selectively target the COX present

Dan Simmon’s group suggest this is be- COMMENTARY genase (COX) enzyme variant that could in the brain (9). Could this explain why cause of the presence of a variant of be the target of acetaminophen and other it was analgesic and antipyretic but not COX-1, which they have named COX-3, ͞ analgesic antipyretic drugs (2). antiinflammatory? that is especially sensitive to acetamino- After 3,500 years, the first real progress The next great step forward in our phen and related compounds (2). If this in our understanding of the mechanism of understanding of the NSAIDs came in the enzyme were particularly expressed in the action of the NSAIDs came 30 years ago, early 1990s with the demonstration that brain, could it explain both the character- when it was revealed that these chemically there were two isoforms of COX: COX-1, istics of acetaminophen and Flower and varied drugs all re- which was constitu- Vane’s findings from 30 years ago (9)? It duced the formation tively expressed, and is difficult to produce an unequivocal re- of prostaglandins. After 3,500 years, the ﬁrst real COX-2, which was in- ply, but let us try to approach an answer by This ability was ducible (1, 5, 10–13). progress in our understanding drawing on what we know about acet- associated with inhi- COX-2 was rapidly aminophen and the roles of COX-1 and -2. bition of COX, which of the mechanism of the up-regulated at in- To begin with, let us consider fever, be- converts arachidonic flammatory sites and NSAIDs came 30 years ago. cause pyresis is a more simply modeled acid to the prosta- appeared responsible process than analgesia. Interestingly, and glandin precursor for the formation at odds with Chandrasekharan et al. (2), prostaglandin (PG) of proinflammatory studies of the prostanoid-producing en- H2 (3). The prostanoid family was re- prostanoids. COX-1, meanwhile, ap- zyme underlying pyresis associate it to vealed through associated studies, and peared to shoulder the responsibility for neither COX-1 protein nor the COX-1 PGH2 was shown to be the precursor for the production of physiologically relevant gene. For instance, in mice, it is deletion of prostanoids including PGD2, PGE2, prostanoids such as those in the stomach the COX-2 but not of the COX-1 gene PGF2␣, PGI2, and thromboxane A2 (4). and platelets (1, 5). Pharmacology defined (which also encodes COX-3) that blunts the selectivity of existing NSAIDs on Understanding that the NSAIDs inhibited pyresis (19). In addition, COX-2-selective prostanoid formation led to an apprecia- these COX enzymes (1, 5, 14, 15) and inhibitors, which will react weakly with the tion of the mechanisms underlying the played a key role in producing a new COX-3 enzymatic site, because it is iden- effects of these drugs. At sites of inflam- generation of COX-2-selective drugs (now tical to that in COX-1, are as good at mation, the local production of prosta- selling in vast quantity). These drugs reducing fever similarly as traditional noids such as PGE can sensitize pain would, it was hoped, be antiinflammato- 2 NSAIDs (20–23). The fever response has nerve endings and increase blood flow, ries as good as the traditional NSAIDs but promoting feelings of pain and driving have much reduced toxic side effects, par- tissue swelling and redness (1, 5). Inhibi- ticularly on the gastrointestinal tract (1, 5). See companion article on page 13926. tion of PGE2 formation via the inhibition Although providing a much-needed †To whom correspondence should be addressed. E-mail: of local COX could therefore explain the leap in our understanding, the COX-1͞-2 [email protected].

www.pnas.org͞cgi͞doi͞10.1073͞pnas.222543099 PNAS ͉ October 15, 2002 ͉ vol. 99 ͉ no. 21 ͉ 13371–13373 Downloaded by guest on September 26, 2021 also been clearly associated with a rapid induction of COX-2 expression and an associated increase in PGE2 production (24), with no role for COX-1 or a COX-1 gene product (e.g., COX-3). Finally, the sites of COX-3 expression do not appear to accord well with those sites associated with fever, and we might expect to see the protein present within the hypothalamus (25) rather than the cerebral cortex. All these considerations appear to argue against the COX-3 of Chandrasekharan et al. (2) being the site of the antipyretic actions of NSAIDs and COX-2-selective agents. However, the results from Chan- drasekharan et al. could be read as show- ing that acetaminophen acts at a different site to the other NSAIDs and that more than one COX isoform contributes to the fever response. Pain is a more difficult process to un- ravel. As outlined above, prostanoids produced at sites of inflammation can sensitize nerve endings and so promote the localized feelings of pain associated with inflammatory events and tissue injury (26). These prostanoids can be produced Fig. 1. A COX continuum? Two distinct genes for COX-1 and -2 may give rise to a number of constitutive by COX-2 induced by the local inflamma- and inducible COX proteins with overlapping functions. Considering prostanoid production by a COX tory processes. How then does acetamin- continuum may help us appreciate which enzymes underlie prostanoid production in different tissues as well as the actions of traditional NSAIDs, newer COX-2-selective drugs, and acetaminophen (‘‘COX-2b,’’ as ophen bring about its analgesic effects, suggested in ref. 33; COX-3, as suggested in ref. 2). because it is not a peripheral antiinflammatory? With the discovery of COX-2, new efforts have been made to compre- Chandrasekharan et al. (2) is that multi- found in the heart and aorta? Or could hend the roles of prostanoids within the ple COX isoenzymes could be derived varied products from just two distinct central nervous system (CNS). It appears from just two distinct genes providing a genes provide a family of COX proteins that COX-2 is constitutively expressed in COX continuum of enzymes and prod- with overlapping contributions to prosta- the CNS and also rapidly up-regulated to ucts (Fig. 1). Could the presence of mul- noid production throughout the body? reinforce pain perception (27, 28). Could tiple isoforms of COX-1 and -2 explain Might both inducible COX-2 and COX-3 acetaminophen act on this CNS enzyme? why there are so many different NSAIDs be involved in the fever response, COX-2-selective inhibitors appear to pro- on the market and why different patients whereas both constitutive COX-2 and duce analgesic responses at least as good appear to benefit from different types of COX-3 contribute to the circulatory pro- as traditional NSAIDs in inflammatory, NSAID? If we express variants of COX-1 duction of PGI ? We know that both dental, or postoperative pain (29–31). 2 and -2, could different drugs inhibit dif- COX-1 and -2 have constitutive roles in These activities would support, as above, a ferent variants to different extents? In- the kidney. All this has yet to be under- role for COX-2 or a COX-2 variant rather deed, could these findings help us un- stood, but as we continue to push toward than a COX-1 variant. But maybe acet- derstand some of the side effects of an understanding, it is important to note aminophen targets an additional enzyme. NSAIDs and COX-2-selective inhibi- We know there may be both redundancy tors? For example, much recent atten- that Chandrasekharan et al.’s study also and compensatory increases in COX en- tion has been paid to the ability of tells us that modifications in regions of zymes; for instance, COX-2 may be up- COX-2-selective inhibitors to reduce the COX molecule other than the enzymatic site may influence inhibitor selec- regulated when COX-1 is inhibited in the circulating PGI2 levels and to the hypoth- stomach (32). Furthermore, Dan Sim- esis that this could be linked to an in- tivity, possibly by affecting the interplay mon’s group has previously proposed the crease in thrombotic risk (35). Interest- with other active intracellular species existence of an isoform of COX-2 that is ingly, acetaminophen also reduces (37). In terms of our 3,500-year quest particularly sensitive to acetaminophen circulating PGI2 levels (36), yet it is not to understand the mechanism of action (33, 34). a selective COX-2 inhibitor. Could this of the NSAIDs, Dan Simmon’s group From the above, it seems that the most PGI2 actually be formed by the COX-3 has provided another significant step significant implication of the study of that Chandrasekharan et al. (2) have forward.

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