Paracetamol

Paracetamol, also known as acetaminophen or APAP, is a medication used to treat fever and mild to moderate pain. It is one of the most used fever and pain-relieving drugs worldwide and its consumption increases everyday.


Genetics

Variation in our genome can contribute to the variable effectiveness of paracetamol as an analgesic, and to its side effects. 

Paracetamol is converted into the liver-toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) already at therapeutic doses, causing hepatotoxicity, a well-known adverse effect of the drug making paracetamol the principal cause of acute liver failure in the Western world.

Paracetamol is degraded in a minor pathway (about 5%) by CYP450s mainly by CYP2E1 and creates NAPQI, which is toxic, and can be eliminated with the help of glutathione (GSTs enzymes), so too much paracetamol can deplete glutathione status. APQI is indeed detoxified by a reaction with reduced glutathione (GSH). After toxic doses of intake, however, GSH is depleted by conjugation. If the GSTM1 gene is absent, this results in a loss of function, poor glutathione transferase activity and inability to neutralise NAPQI. Increasing antioxidants, including glutathione, and addressing inflammation and oxidative stress which deplete glutathione levels further, can be helpful. 

If alcohol is added to the mix, it also gets degraded by CYP2E1 into a toxic substance, which will also damage the liver and will need glutathione even more, which is why drinking is not recommended while taking paracetamol. Starvation and diabetic state increase CYP2E1 activity further increasing risk of NAPQI toxicity and free radical damage. Isothiocyanates, found in foods such as radish, Brussels sprouts, watercress, mustard and wasabi, have been found to reduce CYP2E1 activity.

CYP2D6 is also involved in paracetamol detoxification. Its allele frequency is known to vary strongly amongst ethnic groups, and the activity ranges from complete deficiency to ultrafast metabolism, depending on different known alleles. SNPs that lead to slower metaboliser of substrates such as paracetamol may reduce or delay efficacy, while SNPs that lead to fast (ultra-rapid) metaboliser of paracetamol to NAPQI may increase the risk of toxicity. At Lifecode Gx, we report results of four main alleles. 

Glucuronidation is the major pathway of paracetamol metabolism, as more than 50% is eliminated by this pathway. UGTs has been shown to be an important determinant of acetaminophen bioactivation and toxicity. The glucuronidation pathway transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs (such as paracetamol), into water-soluble, excretable metabolites. SNPs on UGT1A1 may result in possible impaired glucuronidation of paracetamol. Calcium d-glucarate has been shown to improve glucuronidation by inhibiting beta-glucuronidase produced by unhealthy gut bacteria. SNPs on UGT1A6 that increase its activity are beneficial and increase UGT1A6 enzyme activity and protection from harmful carcinogens.

Approximately 30–44% of administered paracetamol is excreted in the urine as sulfate conjugates. SULTs are members of a superfamily of enzymes that catalyze the sulfate conjugation of various endobiotics and xenobiotics, including paracetamol. Polymorphisms on SULT1A1 and SULT1E1 can lead to an impaired sulphoconjugation (detoxification) of paracetamol. Ensure adequate sulphur-containing nutrients (found in garlic, onion, Brussels sprouts and kale) to support this genotype.

Finally, deacetylation of paracetamol by N-deacetylase enzymes takes place mainly in the liver, and then p-aminophenol is converted to AM404 by FAAH in the brain.

Paracetamol is conjugated via the addition of an acetyl group by the N-terminal acetyltransferases (NAT) enzymes. N-deacetylase enzymes have been reported many times to play a role, like CYP450, in paracetamol nephrotoxicity. NAT2 N-Acetyltransferase 2 encodes an enzyme that both activates and deactivates various pharmaceutical drugs such as paracetamol and carcinogens. It is also involved in the detoxification of caffeine. Variants on this gene are associated with slow acetylator phenotypes and higher incidence of cancer and drug toxicity. The two-SNP genotype panel of rs1041983 and rs1801280 enables assessment of rapid vs slow acetylation. A slow NAT2 activity increases the susceptibility to side effects from paracetamol.

P-aminophenol is then converted to AM404 (N-arachidonoylphenolamine) by FAAH in the brain. Paracetamol needs a FAAH-dependent metabolism to exert its antinociceptive effect. A SNP on FAAH resulting in decreased enzyme activity could alter the therapeutic (analgesic and antipyretic) effects of paracetamol.

Lifecode Gx® Reports

Our Detoxification Report shows your Paracetamol Detoxification results and explains how nutrigenomics can help with unpleasant symptoms.

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