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Paracetamol Metabolism Pathways

Paracetamol is primarily metabolized in the liver into non-toxic compounds through three pathways: glucuronidation, sulfation, and N-hydroxylation/GSH conjugation. The cytochrome P450 enzymes metabolize a small amount of paracetamol into NAPQI, a toxic intermediate. NAPQI is then conjugated by glutathione, but an overdose can overwhelm this pathway, allowing NAPQI to accumulate and cause toxicity. Individuals' rates of NAPQI production may vary due to genetic differences in their CYP450 enzyme expression.

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950 views2 pages

Paracetamol Metabolism Pathways

Paracetamol is primarily metabolized in the liver into non-toxic compounds through three pathways: glucuronidation, sulfation, and N-hydroxylation/GSH conjugation. The cytochrome P450 enzymes metabolize a small amount of paracetamol into NAPQI, a toxic intermediate. NAPQI is then conjugated by glutathione, but an overdose can overwhelm this pathway, allowing NAPQI to accumulate and cause toxicity. Individuals' rates of NAPQI production may vary due to genetic differences in their CYP450 enzyme expression.

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Paracetamol metabolism Paracetamol is metabolised primarily in the liver, into non-toxic products.

Threemetabolic pathways are notable:


Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[73] Sulfation (sulfate conjugation) may account for 2040%.[73] N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known asNAPQI (N-acetyl-p-benzo-quinone imine).[74] NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.[74]

All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an example of toxication.
Paracetamol will be metabolised largely inside the liver organ, directly into non-toxic goods. A few metabolic path ways are usually noteworthy: Glucuronidation will be considered to are the cause of 40% to be able to two-thirds of the metabolic rate of paracetamol. Sulfation (sulfate conjugation) may well are the cause of 2040%. N-hydroxylation and also rearrangement, next GSH conjugation, balances at under 15%. The hepatic cytochrome P450 enzyme method metabolizes paracetamol, building a but considerable alkylating metabolite called NAPQI (N-acetyl-p-benzo-quinone imine). NAPQI will be next irreversibly conjugated with all the sulfhydryl sets of glutathione. Almost all a few path ways produce ultimate goods which can be sedentary, non-toxic, and in the end excreted from the kidneys. Inside the next walkway, nonetheless, the more advanced merchandise NAPQI will be dangerous. NAPQI will be largely in charge of the dangerous outcomes of paracetamol; this kind of what people mean about among toxication. Creation of NAPQI is born largely to be able to a couple of isoenzymes of cytochrome P450: CYP2E1 and also CYP1A2. The P450 gene will be very polymorphic, nonetheless, and also personal distinctions inside paracetamol toxicity are usually considered to be because of next isoenzyme, CYP2D6. Innate polymorphisms inside CYP2D6 may well give rise to substantially diverse costs of creation of NAPQI. Moreover, men and women may be labeled since "extensive", "ultrarapid", and also "poor" metabolizers (producers of NAPQI), according to their particular numbers of CYP2D6 appearance. Despite the fact that CYP2D6 metabolises paracetamol directly into NAPQI with a smaller level as compared to some other P450 digestive enzymes, the action may well give rise to paracetamol toxicity inside substantial and also ultrarapid metabolisers, when paracetamol will be obtained with huge amounts. With normal amounts, NAPQI will be swiftly detoxified simply by conjugation. Pursuing overdose, and perchance furthermore inside substantial and also ultrarapid metabolizers, this kind of cleansing walkway will become over loaded, and also, for that reason, NAPQI amasses.

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