Prostaglandin-endoperoxide synthase 3 (COX-3) (PTGS3)

Prostaglandin-endoperoxide synthase 3 (PTGS3), commonly known as COX-3, is a splice variant of the PTGS1 (COX-1) gene that was historically proposed as the primary molecular target for acetaminophen (paracetamol) [Chandrasekharan et al., 2002]. It was first identified in the canine cerebral cortex, where the retention of intron 1 in the PTGS1 mRNA produces a functional enzyme sensitive to non-steroidal anti-inflammatory drugs (NSAIDs) and antipyretics [Schwab et al., 2003]. In humans, however, the retention of this intron introduces a frameshift mutation that results in a truncated protein lacking catalytic activity, making it a non-functional genetic product [Daba et al., 2004]. The 'COX-3 hypothesis' was initially popular because it provided a potential explanation for the central analgesic effects of acetaminophen without the peripheral anti-inflammatory side effects typical of COX-1 and COX-2 inhibitors [Botting, 2006]. Despite this, extensive biochemical and genetic studies have failed to demonstrate the existence of a functional COX-3 protein in human tissues [Snijdewint et al., 2005]. Consequently, PTGS3 is not considered a valid therapeutic target in human pharmacology, and the effects of acetaminophen are now attributed to other mechanisms, such as the modulation of the endocannabinoid system or the inhibition of COX enzymes in specific cellular environments [Graham et al., 2013].

Other names

Cyclooxygenase-3COX-3PTGS1 splice variantPTGS1b

Proposed inhibition of prostaglandin synthesis specifically within the central nervous system, potentially through interaction with a splice variant of COX-1 [Chandrasekharan et al., 2002].