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NAPQIN-Acetyl-P-Benzoquinone Imine
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El exceso de exposicion de las celulas al NAPQI conduce a un deterioro progresivo de la funcion celular.
When administered early after an acute APAP overdose, NAC provides cysteine for the replenishment and maintenance of hepatic glutathione stores, enhances the sulfation pathway of elimination, and may directly reduce NAPQI back to acetaminophen [31, 32].
In animal models, it was observed that glutathione depletion and covalent binding of NAPQI were insufficient to cause hepatocyte death with hepatotoxic doses of acetaminophen, but JNK was required to actively induce programmed necrosis (Garcie-Cortes et al.
However, when APAP was taken-in an overdose, the rate of formation of NAPQI was greatly increased and hepatic glutathione level was decreased which lead to liver dysfunction (Mitchell et al., 1973).
The toxic metabolite of APAP is NAPQI. In therapeutic dose, this metabolite is detoxified by conjugating with glutathione.
Moreover, such strategies suggest that phytochemicals may interfere with APAP metabolism by suppressing CYP2E1 activity and preventing generation of NAPQI, thus making the interpretation of these studies difficult [40, 41].
In high doses of APAP, the oxidation pathway is initiated by the formation of the reactive metabolite NAPQI, which is generated mainly by the cytochrome P450 enzymes Cyp2e1 in mice and humans [3].
Also hepatic oxidation of paracetamol by CYP1A2,3A4, and 2E1 generates the highest reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) which is conjugated by glutathione into a renal metabolite that becomes safe.
AAN is caused by accumulation of a toxic metabolite, NAPQI. d.
This generates NAPQI in amounts that can deplete glutathione, which, if not replenished, results in the accumulation of NAPQI in the hepatocytes.7 Secondary to NAPQI-induced glutathione depletion and oxidative stress, lipid peroxidation takes place which leads to irreversible cell membrane injury and, hence, cell death.7,8
At therapeutic doses, most APAP is metabolized by cytochrome P450 enzymes to form the highly reactive intermediate metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is readily detoxified via conjugation with glutathione (GSH) under normal conditions.