Cyclooxygenase-3: axiom, dogma, anomaly, enigma or splice error?--Not as easy as 1, 2, 3.

A continued need to develop safe and effective analgesics and anti-inflammatory drugs fuels the ongoing investigations of cyclooxygenase (COX). In addition, a long unanswered question in the biomedical arena revolves around the mechanism of action of acetaminophen leading to its analgesic and antipyretic activity. Upon the discovery of COX in 1971, alternative enzyme forms were initially suggested. With the development of molecular biology, the discovery of two major cyclooxygenase genes (COX-1 and COX-2) was heralded in 1990, which has subsequently led to the clinical use and development of selective COX-2 inhibitors. Splice variants of both COX-1 and COX-2 were first encountered in the early 1990s, as were single nucleotide polymorphisms of COX-1 and 2. There have been some recently well-publicized investigations of COX-1 and -2 enzyme variants that may assist in our eventual conceptual understanding of the mechanisms of action of acetaminophen. The term "COX-3" has been utilized by some scientists and in the media. The evidence for "COX-3" in terms of various COX-variants and possible scientific and therapeutic implications of COX variant enzymes are described.