ed by members of the cytochrome P450 phase I biotransformation enzymes. The products are taken up by various liver efflux transporters and eliminated via excretion. It is generally accepted that the mode of action of paracetamol is the inhibition of prostanoid biosynthesis, particularly prostaglandins, via the cyclooxygenase (COX) mediated pathway of arachidonic acid metabolism (lipooxygenases and cytochrome P450 monooxygenases mediate the other two routes to produce leukotriene and other metabolites). The Ptgs1 and Ptgs2 cyclooxygenases, better known as Cox1 and Cox2 are bifunctional enzymes that in addition to the first cyclooxygenase activity, carry out a second, peroxidase activity. In the first reaction arachidonic acid is oxidized to prostaglandin G2 (PGG2) - a reaction dependent on a tyrosine radical on the enzyme, the generation of which involves the peroxidase activity. PGG2 is converted to prostaglandin H2 (PGH2) in the second, peroxidase mediated reaction. PGH2 is the substrate for various, cell specific enzymes that produce the final prostaglandins, prostacyclin and thromboxane, collectively known as prostanoids. Under conditions of low arachidonic acid concentrations, Cox2 pathway is preferentially activated, which explains the apparent 'selectivity' of paracetamol for this enzyme. Cox 1 is a constitutive enzyme whereas Cox 2 is inducible. Cox2 can also act upon the endogenous endocannabinoids providing a route for their degradation. Prostanoids bind to and activate the prostanoid receptors, G-protein coupled (GPCRs) to elicit a vast range of responses including sensitization to pain, inflammation and fever, immune and cardiovascular functions. The Cox enzymes are targets of various non-selective non-steroidal anti-inflammatory (NSAID) and selective Cox-2 inhibitor drugs. Overall, paracetamol is a weaker analgesic than both NSAIDs or the specific inhibitors, but is preferred because of its better tolerance. NSAIDs and the specific Cox inhibitors interfere with the first, cyclooxygenase activity whereas paracetamol interferes with the second, peroxidase activity. A Cox-induced formation of a paracetamol phenoxyl radical competes with the oxidation of the tyrosine residue on the enzyme to produce the tyrosine phenoxyl radical, essential for the cyclooxygenase function. In addition, another bioactive metabolite of paracetamol - arachidonyl-aminophenol (AM404) can inhibit endocannabinoid uptake and while considered a mediator of paracetamol effects, the mechanisms of its function are a matter of debate. Excessive paracetamol and subsequent increase in NAPQI and GSH conjugation leads to GSH depletion in the cell. Glutathione depletion can have serious consequences as GSH is an important cellular antioxidant. This and possibly the formation of adducts with other cellular proteins, which can take place once enough glutathione stores have been depleted, are thought to underlie the hepatotoxicity of paracetamol. Paracetamol overdose causes oxidative stress, mitochondrial dysfunction and hepatocyte necrosis. It can also be nephrotoxic and cause renal failure, although to a lesser extent. N-acetylcysteine is being as an antidote and several plant extracts are being assessed for their potential therapeutic effects in rat animal models To see the ontology report for annotations, GViewer and download, click here...(less)