Top Gene Interactions
- Metabolism: Acetaminophen primarily undergoes glucuronidation (45-55% of the dose) in which this process is facilitated by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver or UGT1A10 in the gut. 30-35% of the dose undergoes sulfation. This biotransformation is facilitated by SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. A small percentage of acetaminophen is oxidized by CYP2E1 to form N-acetyl-p-benzo-quinone imine (NAPQI), a toxic metabolite which is then conjugated to glutathione and excreted renally. Studies suggest that CYP3A4 and CYP2E1 are the primary cytochrome P450 isozymes responsible for the generation of toxic metabolites. Accumulation of NAPQI may occur if primary metabolic pathways are saturated. Acetaminophen is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion is metabolized via the hepatic cytochrome P450 enzyme system. The toxic effects of acetaminophen are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine), not acetaminophen itself nor any of the major metabolites. This toxic metabolite reacts with sulfhydryl groups. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys. The toxic dose of paracetamol is highly variable. Route of Elimination: Approximately 80% of acetaminophen is excreted in the urine after conjugation and about 3% is excreted unchanged. Half Life: 1 to 4 hours
- Uses/Sources: An over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies.
- Health Effects: Skin rashes, blood disorders and a swollen pancreas have occasionally happened in people taking the drug on a regular basis for a long time.
- Symptoms: When taken at the recommended dose, side-effects of paracetamol are rare. Skin rashes, blood disorders and a swollen pancreas have occasionally happened in people taking the drug on a regular basis for a long time. The signs and symptoms of paracetamol toxicity occur in three phases. The first phase begins within hours of overdose, and consists of nausea, vomiting, pallor, and sweating. Rarely, after massive overdoses, patients may develop symptoms of metabolic acidosis and coma early in the course of poisoning.The second phase occurs between 24 and 72 hours following overdose and consists of signs of increasing liver damage. In general, damage occurs in hepatocytes as they metabolize the paracetamol. The individual may experience right upper quadrant pain. Acute kidney failure may also occur during this phase, typically caused by either hepatorenal syndrome or multiple organ dysfunction syndrome. The third phase follows at 3 to 5 days, and is marked by complications of massive hepatic necrosis leading to fulminant hepatic failure with complications of coagulation defects, hypoglycemia, kidney failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death.
- Treatment: In adults, the initial treatment for paracetamol overdose is gastrointestinal decontamination. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe. Gastric lavage, better known as stomach pumping, may be considered if the amount ingested is potentially life-threatening and the procedure can be performed within 60 minutes of ingestion. Acetylcysteine, when used early in the course of treatment, reduces morbidity and virtually eliminating mortality associated with even a massive acetaminophen overdose. (L1712) In patients who develop fulminant hepatic failure or who are otherwise expected to die from liver failure, the mainstay of management is liver transplantation.
- Route of Exposure: Oral, rapid and almost complete.
- Carcinogenicity: 3, not classifiable as to its carcinogenicity to humans. (L135)
- Toxicity: LD50: 338 mg/kg (Oral, Mouse) (A308) LD50: 1944 mg/kg (Oral, Rat) (A308) In adults, single doses above 10 grams or 200 mg/kg of bodyweight, whichever is lower, have a reasonable likelihood of causing toxicity.
- Lethal Dose: 25 g for an adult human. (A308)
Mechanism of Action
|Target Name||Mechanism of Action||References|
Thioredoxin reductase 1, cytoplasmic
Glutathione peroxidase 1
Carbonic anhydrase 1
Thioredoxin reductase 2, mitochondrial
Thioredoxin reductase 3
Cytochrome P450 3A4
Cytosolic 10-formyltetrahydrofolate dehydrogenase
Cytochrome P450 2E1
Carbonic anhydrase 2
Carbonic anhydrase 4
Carbonic anhydrase 3
Cytochrome P450 1A1
Carbonic anhydrase 9
Carbonic anhydrase 12
Carbonic anhydrase 14
Carbonic anhydrase 5A, mitochondrial
Carbonic anhydrase 5B, mitochondrial
Carbonic anhydrase 6
Carbonic anhydrase 7
Aldehyde dehydrogenase, mitochondrial
Glutamate dehydrogenase 1, mitochondrial
Glycerol-3-phosphate dehydrogenase [NAD(+)], cytoplasmic
Glycerol-3-phosphate dehydrogenase, mitochondrial
Arachidonate 5-lipoxygenase-activating protein
Prostaglandin G/H synthase 1
Prostaglandin G/H synthase 2
|Acetaminophen is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1 and COX-2, enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects. While aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Studies also report data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works.||