How does NAPQI differ from paracetamol?
Paracetamol (acetaminophen) is toxic because its breakdown products form a compound that reacts with the glutathione. The breakdown product, N-acetyl-p-benzo-quinone imine; NAPQI) reacts with the sulphydryl groups of glutathione, which are used up by the excessive amount of breakdown product.
What does NAPQI do to cells?
In this capacity, it protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI begins to react with the cellular proteins, killing the cells in the process.
How is NAPQI formed?
The formation of NAPQI may proceed via CYP2E1 [56] and via peroxidases such as prostaglandin hydroperoxidase. The most commonly described mechanism proposes that metabolic activation occurs through N-oxidation of acetaminophen to N-hydroxyacetaminophen followed by dehydration to NAPQI (Figure 25.23) [57].
How is acetaminophen metabolized?
Acetaminophen is extensively metabolized by the liver via three main hepatic pathways: glucuronidation, sulfation, and CYP450 2E1 oxidation. Approximately 90% of acetaminophen is conjugated to sulfated and glucuronidated metabolites that are renally eliminated.
How is NAPQI excreted?
NAPQI is highly reactive and is primarily responsible for acetaminophen-induced hepatotoxicity. Detoxification of NAPQI occurs through its binding to the sulfhydryl group of glutathione (GSH) to form APAP-GSH, which is ultimately excreted in the urine as cysteine and mercapturic acid conjugates (APAP-cys) [5,9].
Is NAPQI a ros?
These observations support the hypothesis that complex I is a critical source of ROS leakage in APAP hepatotoxicity. Mitochondrial oxidative stress and signaling in APAP hepatotoxicity. Metabolism of APAP forms the reactive metabolite NAPQI, which targets proteins, especially mitochondrial proteins.
What is Glucuronidation reaction?
Glucuronidation is a conjugation reaction whereby glucuronic acid, derived from cofactor UDP-glucuronic acid, is covalently linked to a substrate containing a nucleophilic functional group. The resultant metabolite, called a glucuronide, is usually excreted in bile and urine.
How does NAC detoxify NAPQI?
The antidote for acetaminophen poisoning, NAC, is theorized to work through a number of protective mechanisms. Since NAC is a precursor of glutathione, it increases the concentration of glutathione available for the conjugation of NAPQI.
Where is Tylenol metabolized?
At therapeutic doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates that are then excreted in the urine.
How quickly is acetaminophen metabolized?
Acetaminophen is rapidly absorbed from the GI tract with peak plasma levels usually occurring at 2 hours and almost always by 4 hours. Once absorbed, acetaminophen is metabolized by the liver by glucoronidation (60%), sulfation (30 %), and a small amount (4 – 7 %) is excreted unchanged in the urine.
How is NAPQI toxic?
Since glutathione is depleted by the metabolite NAPQI in acetaminophen-induced hepatotoxicity and glutathione is the cofactor for glutathione peroxidase detoxification of peroxides, a major mechanism of peroxide detoxification is compromised in acetaminophen-induced toxicity.
How does glutathione neutralize NAPQI?
Detoxification of NAPQI occurs through its binding to the sulfhydryl group of glutathione (GSH) to form APAP-GSH, which is ultimately excreted in the urine as cysteine and mercapturic acid conjugates (APAP-cys) [5,9].