Environmental Toxins and Chronic Illness
Aruna Bakhru in Nutrition and Integrative Medicine, 2018
As stated by Paracelsus several hundred years ago, “All things are poison and nothing is without poison, only the dose permits something not to be poisonous” (Mattson and Calabrese, 2010). In more modern terms, according to Croom (2012), “The dose makes the poison.” The author goes on to point out that, as the dose shifts from low to high of any particular substance, there is a change in the relative importance of various detoxification enzymes involved in metabolism of the substance. Croon (2012) then presents an example of this. For acetaminophen, lower therapeutic doses go through the phase II pathways glururonidation and sulfotransferase conjugation. However, higher doses overwhelm the cofactors available for phase II conjugation, leaving the phase I pathway CYP2E1 to become predominant. Unfortunately, CYP2E1 activity leads to the formation of the highly reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). According to Liska et al. (2005), NAPQI is a highly neurotoxic substance that, if not cleared by glutathione conjugation, can lead to severe toxicity.
Complications of Postoperative Pain and Pain Management
Stephen M. Cohn, Matthew O. Dolich in Complications in Surgery and Trauma, 2014
Acetaminophen is widely prescribed for surgical pain management and fever, and is contained in a large number of preparations and opioid compounds. Accidental or intentional acetaminophen overdose (7.5–10 g in adults; >150 mg/kg in children) can cause hepatotoxicity, which is the most common cause of acute liver failure in United States [52]. Toxicity from acetaminophen is not from the drug itself but from one of its metabolites, N-acetyl-p-benzoquinone imine (NAPQI). Normally this metabolite undergoes conjugation with glutathione, but at toxic doses conjugation depletes glutathione, leading to hepatic cell necrosis. Symptoms related to NAPQI hepatotoxicity including anorexia, nausea, vomiting, right upper quadrant pain, diaphoresis, jaundice, and hypoglycemia may develop over 1–5 days [52]. Treatment of acetaminophen overdose includes administration of oral-activated charcoal to decrease absorption of acetaminophen and N-acetyl cysteine—as an antidote, which act as a precursor for glutathione. Acetaminophen is absolutely contraindicated in patients in fulminant hepatic failure, and restricted for use in chronic alcohol abusers. Acetaminophen should be used with caution in patients with severe hepatic impairment, although hepatotoxicity has not been shown to occur at the recommended doses. In patients with severe renal impairment, the minimum interval redosing of the drug should be increased to 6 h [53,54].
Interaction of Alcohol with Medications and Other Drugs
John Brick in Handbook of the Medical Consequences of Alcohol and Drug Abuse, 2012
The over-the-counter (OTC) medication acetaminophen (Tylenol) is one of the most commonly consumed medications in the United States because of its effective analgesic and antipyretic properties. Acetaminophen is metabolized by the CYP2E1 isozyme to a toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by the antioxidant glutathione (Kuffner, 2001). Chronic alcohol use reduces the amount of the glutathione produced in the liver cell mitochondria. When a person ingests large amounts of acetaminophen and/or has reduced glutathione levels resulting from chronic alcohol use, the amount of NAPQI produced overwhelms the detoxification system of the liver. The resulting hepatotoxicity may progress to the point of fulminant hepatic failure and death.
The pharmacological management of dental pain
Published in Expert Opinion on Pharmacotherapy, 2020
Joseph V. Pergolizzi, Peter Magnusson, Jo Ann LeQuang, Christopher Gharibo, Giustino Varrassi
Acetaminophen (also known as paracetamol) is one of the most frequently used analgesic and antipyretic agents and has few adverse effects at therapeutic doses but can cause potentially life-threatening hepatotoxicity at high doses. Acetaminophen is metabolized mainly by the liver via glucuronidation or sulfation, producing nontoxic metabolites, but about 5% of the therapeutic doses is metabolized by way of the cytochrome P450 (CYP450) enzymatic system (mainly but not exclusively CYP2E1) to produce the N-acetyl-p-benzoquinone imine (NAPQI) metabolite. NAPQI is potentially toxic to the liver, but in small quantities it is rapidly conjugated with glutathione and excreted by the kidneys. When large quantities of NAPQI are produced, as with an overdose of acetaminophen, NAPQI builds up in the liver and can cause necrosis and apoptosis [4].
Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series
Published in Clinical Toxicology, 2022
Stephanie L. Link, Garrett Rampon, Stephen Osmon, Anthony J. Scalzo, Barry H. Rumack
APAP became first widely available in the United States (US) in the 1950s; it was marketed as the first aspirin free pain reliever. Currently APAP is the most common drug ingredient in America and is found in more than 600 different prescription and over the counter medications. Fifty million Americans use APAP each week [8]. APAP is widely available in multiple forms including capsules, suppositories, and intravenous. The maximum recommended therapeutic dose of APAP in adults is 4 grams per day or less and approximately 50 to 75 mg/kg/day in children [9]. The metabolism of APAP involves converting APAP to nontoxic sulfate and glucuronide conjugates, and a small portion is converted to the potentially toxic N-acetyl-p- benzoquinone imine (NAPQI). NAPQI is a highly reactive species that causes hepatotoxicity in APAP overdose when it cannot be bound by cytosolic glutathione and eliminated as the mercapturate [10]. Once glutathione is depleted, mitochondrial protein adducts may be formed which can lead to cell death via a mitogen activated protein (MAP) kinase cascade dependent process that activates c-Jun N-terminal kinase (JNK) via phosphorylation in the cytosol. This activated JNK allows for translocation to the mitochondria resulting in further reactive oxygen species, mitochondrial swelling, and other events which leads to hepatotoxicity [11].
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
This mechanism was subsequently modified following reports by Dr. Ian Calder’s laboratory in Australia that N-acetyl-p-benzoquinone imine (NAPQI) was an electrophilic species (Calder et al. 1973, 1974, 1981). They were able to synthesize it by oxidation with lead tetra-acetate, but it rapidly decomposed. Identification was indirect as a Diels–Alder adduct (Calder et al. 1973). Based on their findings that it was a reactive species, Mitchell and coworkers subsequently postulated that APAP was initially N-hydroxylated by cytochrome P450 to form N-hydroxy-APAP, which then spontaneously dehydrated to form NAPQI (Figure 3). Thus, the reactive toxic metabolite that covalently bound to protein was hypothesized to be NAPQI, and the binding site in proteins was postulated to be cysteine (Hinson 1980; Streeter et al. 1984).
Related Knowledge Centers
- Acute Liver Failure
- Cyp2E1
- Cyp3A4
- Drug Metabolism
- Glucuronidation
- Paracetamol
- Cytochrome P450
- Glutathione
- Analgesic
- Paracetamol Poisoning