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How is NAPQI produced?

How is NAPQI produced?

NAPQI, also known as NAPBQI or N-acetyl-p-benzoquinone imine, is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and then almost immediately detoxified in the liver.

What does NAPQI do to cells?

When the glutathione is completely used up, the NAPQI begins to react with liver cell proteins, killing the cells. It causes necrosis in the liver cells and kidney tubules. This same principle occurs in mushroom or toadstool poisoning.

Which metabolic pathway is responsible for NAPQI?

We were able to use this model system to study both variation in the “GSH pathway,” the major metabolic pathway known to be responsible for NAPQI detoxification, as well as the possible association of genome-wide SNPs with NAPQI IC50 values.

What is the mechanism of acetaminophen toxicity?

Patients at Increased Risk. Because the mechanism of acetaminophen toxicity occurs via the formation of NAPQI, any factors that influence the availability of metabolic enzymes will therefore affect toxicity.

How is NAPQI detoxified?

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].

How do you detox NAPQI?

What is the mechanism of liver toxicity by acetaminophen?

APAP hepatotoxicity is initiated by its conversion to the reactive intermediate NAPQI, which results in glutathione depletion and formation of APAP protein adducts. Adduct formation on mitochondrial proteins modulates respiratory chain function, producing elevated levels of free radicals such as superoxide.

What is the most important toxicity of acetaminophen?

In adults, an acute ingestion of more than 150 mg/kg or 12 g of acetaminophen is considered a toxic dose and poses a high risk of liver damage. In children, acute ingestion of 250 mg/kg or more poses significant risk for acetaminophen-induced hepatotoxicity.

Is NAPQI a ros?

Mitochondrial complex I is a crucial site of ROS formation in mitochondria [54], [55], [56]. Metabolism of APAP forms the reactive metabolite NAPQI, which targets proteins, especially mitochondrial proteins.

What is the most found substance in urine after biotransformation of paracetamol?

In adults, paracetamol is almost exclusively metabolized by the hepatic route and excreted into urine, with paracetamol glucuronide (47–62%) and paracetamol sulphate (25–36%) as the main metabolites.

What is the mechanism by which NAPQI toxicity results?

The mechanism by which toxicity results is complex, but is believed to involve reaction between unconjugated NAPQI and critical proteins as well as increased susceptibility to oxidative stress caused by the depletion of glutathione.

How does NAPQI react with glutathione to kill cells?

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. When the glutathione is completely used up, the NAPQI begins to react with liver cell proteins, killing the cells.

How is NAPQI conjugated with glucuronide metabolites?

Large doses of acetaminophen overwhelm the sulfide and glucuronide conjugation pathways and lead to increased formation of active metabolite (Hjelle and Grauer, 1986; Dahm and Jones, 1996; Sturgill and Lambert, 1997; MacNaughton, 2003; Roder, 2004a ). NAPQI is usually conjugated with GSH, as noted above.

Where does NAPQI get produced in the liver?

Many P450 enzymes catalyze the production of NAPQI from APAP [ 14, 15 ]. In our model, NAPQI is produced in the liver by three cytochrome oxidases, CYP2E1, CYP3A4, and CYP1A2. We assume each is Michaelis-Menten and take the K m values from [ 16 ]. Cyp3A4 dominates by having a much larger V max than the other two enzymes.