COX-3 - another COX protein

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The COX ContinuumAlternative splicing may influence the inflammatory response | By Mark Greener

Adapted from T.D. Warner et al., Proc Natl Acad Sci, 99:13371-3, 2002.

SLIDING SCALE: Two distinct genes for COX-1 and -2 may give rise to a number of constitutive and inducible COX proteins with overlapping functions.

The discovery of cyclooxygenase (COX) isoforms, COX-1 and COX-2, in the early 1990s helped explain how non-steroidal anti-inflammatory drugs (NSAIDs) work and led to specific agents with fewer gastrointestinal side effects. Last year, Brigham Young University researchers characterized another isoform, COX-3, which may constitute part of acetaminophen's long sought-after mode of action.1 The study also suggests that a continuum of COX protein products could contribute to common inflammatory disease symptoms and may lead to a new generation of anti-inflammatory drugs.

For 3,500 years, traditional healers used plants containing salicylates. Bayer introduced acetyl-salicylic acid (Aspirin) in 1899, but NSAIDs' mode of action remained a mystery. Then, in 1971, British Nobel Prize winner John Vane discovered that NSAIDs inhibit COX, the rate-limiting enzyme in the synthesis of prostaglandins and other prostanoids.

Roughly 20 years later, re-searchers identified the two COX isozymes, COX-1 and COX-2. Constitutively expressed COX-1 is a physiological housekeeper, protecting the stomach and modulating platelet aggregation, among other actions. Several cytokines induce COX-2 expression, thereby generating inflammatory prostaglandins. NSAIDs counter pain and inflammation by blocking both isozymes, but they also can cause potentially fatal gastrointestinal events. Pharmaceutical companies then developed COX-2-specific inhibitors, which are effective painkillers but spare the gut.

Not every finding fit this neat model, however. Acetaminophen--an effective analgesic and antipyretic, like the NSAIDs, but a weak anti-inflammatory--is not especially active against either COX-1 or COX-2. Furthermore, constitutively expressed COX-2 plays several physiological roles, such as maintaining renal fluid balance. Now, the characterization of COX-3 and other splice variants opens new avenues of understanding.

THE NEW COX COX-3 was isolated along with two smaller so-called partial COX-1 (PCOX-1) proteins.1 COX-3 and PCOX-1 seem to be splice variants derived from COX-1. The researchers showed that acetaminophen, some other analgesics and antipyretics, and several NSAIDS inhibit COX-3. They note, however, that splice variants from COX-2 also might contribute to acetaminophen's actions.

Indeed, splice variants derived from COX-1 and COX-2 could yield a continuum of products with overlapping contributions to prostaglandin production. Timothy Warner at the William Harvey Research Institute, University of London, recently proposed this continuum.2 "We suggest that maybe different variants from the COX-1 and COX-2 genes could underlie constitutive and inducible prostanoid production," he says. This paradigm seems widespread in nature. Warner comments that products from roughly one-third of human genes might undergo alternative splicing.

Such a continuum could help answer some fundamental clinical questions, including why patients differ in the progression of inflammatory disease. "A COX continuum may be present as a fine-tuned system of graded inflammatory responses," says Jan Schwab, a COX researcher at the Institute of Brain Research, Tübingen, Germany. He notes that future studies need to characterize expression of the splice variants during chronic and acute inflammation. Also, polymorphisms that alter splice variant expression could predispose patients to differences in disease progression. "Genetically defined variations might account for differences of the intensity of inflammatory disease progression," Schwab says. A research group at the Harvey institute is exploring whether COX-3 contributes to remission in inflammatory diseases.

Alternative splicing also could help explain why patients benefit from different NSAIDs. "We know that small substitutions in the active site of COX-1, for example, Ile [isoleucine] for Val [valine], produce the different active site found in COX-2," Warner says. So small changes, be they splice variants or mutations, may produce dramatic effects. "Mutations such as these might underlie the reason why different patients appear to prefer different NSAIDs, but I haven't seen hard scientific data to back up the idea."

As some researchers work to fill those knowledge gaps, others are working toward developing better anti-inflammatory agents. Warner notes that any gains from new-generation drugs would be in safety, tolerability, or tissue targeting. "We appear to have reached the ceiling of therapeutic benefit that can follow from COX inhibition," he says. But, says Regina Botting, also at the Harvey institute, "An analgesic with a greater potency in humans ... would also be an advantage. Some drug companies are already interested in pursuing this goal."

Mark Greener (markgreener1@aol.com) is a freelance writer in Cambridgeshire, UK.

References

1. N.V. Chandrasekharan et al., "COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression," Proc Natl Acad Sci, 99:13926- 31, 2002.

2. T.D. Warner et al., "Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?" Proc Natl Acad Sci, 99:13371- 3, 2002.