Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

Heard, Kennon; Green, Jody L.; James, Laura P.; Judge, Bryan S.; Zolot, Liza; Rhyee, Sean H.; Dart, Richard C.

doi:10.1186/1471-230x-11-20

Cited by 101 publications

(115 citation statements)

References 13 publications

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“…Ten of the enrolled subjects in our experiment had measurable protein-derived APAP-CYS serum concentrations, although none demonstrated APAP-CYS protein adducts considered clinically alarming (>1 ng/mL) [2,7].…”

Section: Discussionmentioning

confidence: 88%

“…There is data to indicate that APAP-CYS protein adducts form as a byproduct of simple hepatocellular exposure (not overdose) to APAP in the form of NAPQI [2,6].…”

Section: Discussionmentioning

confidence: 99%

“…3-para-cysteinyl APAP has been demonstrated in human patients with fulminant hepatic failure thought to be related to APAP, as well as following acute overdose of APAP [2] and after ingestion of therapeutic doses of APAP in 4 g/day doses [4,6,7,8].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies over the past decade [2,6] describe a dose-dependent generation of APAP-CYS protein adducts; their diagnostic significance, however, is unclear. The presence of APAP-CYS protein adducts indicates recent ingestion of or exposure to acetaminophen.…”

Section: Discussionmentioning

confidence: 99%

“…Protein-derived APAP-CYS has been isolated in the sera of patients following recommended (therapeutic) doses of APAP and following APAP overdose with and without accompanying liver injury [2].…”

Section: Introductionmentioning

confidence: 99%

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Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

et al. 2015

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Generation of protein-derived acetaminophencysteine (APAP-CYS) is reported after ingestion of large and therapeutic dosages of acetaminophen in healthy and in liver-damaged patients. The incidence of proteinderived APAP-CYS adducts in repeated supratherapeutic dosages of APAP is not known. Methods: for 12 months, a standardized and comprehensive questionnaire was used to interview every consecutive patient at a pain management clinic. Patients found to ingest more than 4 g of APAP per day for a minimum of 14 consecutive days at the time of the encounter were invited to have blood drawn for hepatic transaminases and APAP-CYS adduct levels. Twelve subjects out of 990 interviewees met inclusion criteria. Ten of the 12 had measurable protein-derived APAP-CYS, none had evidence of liver injury. Patients that ingest repeated supratherapeutic amounts of APAP over several weeks may generate APAP-CYS protein adducts in the absence of hepatic injury.

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Section: Discussionmentioning

confidence: 88%

“…There is data to indicate that APAP-CYS protein adducts form as a byproduct of simple hepatocellular exposure (not overdose) to APAP in the form of NAPQI [2,6].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

et al. 2015

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Biomarkers of Mitochondrial Injury After Acetaminophen Overdose

Woolbright

Jaeschke

2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Acetaminophen‐Induced Liver Damage in Hepatic Steatosis

García-Román

Francés

2019

Clin Pharma and Therapeutics

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One of the most used painkillers is acetaminophen (APAP), which is safe at the right dose. However, several studies have described populations susceptible to APAP-induced liver damage, mainly in livers with steatosis. Thus, clinicians should consider the presence of obesity and other chronic liver diseases like nonalcoholic fatty liver disease (NAFLD) when indicating treatment with APAP. Liver damage from this drug is generated through its metabolite N-acetyl-pbenzoquinone imine, which is detoxified with glutathione (GSH). Prior depletion of GSH in steatotic hepatocytes plays a key role in APAP-induced hepatotoxicity in people with obesity and NAFLD. The knowledge about the damage to the liver or APAP in susceptible people like the obese and those with NAFLD is of great relevance for the sanitary sector because it would imply strategies of different therapeutic approach in such patients. This paper reviews the role of APAP in liver damage in the presence of obesity, NAFLD, and nonalcoholic steatohepatitis.Since it was first introduced in clinical practice in 1955, acetaminophen-also known as APAP or paracetamol-has become the most commonly used analgesic/antipyretic in the world. At a therapeutic dose (< 4 g/day in adults, or < 60-75 mg/kg/day in children), it is considered safe and very effective. However, at doses exceeding 4 g/day, it can cause potentially fatal acute liver injury (ALI). The first cases of APAP-induced hepatotoxicity, due to either intentional or accidental ingestion, date back to 1966. 1 Since then, APAP has been considered the principal cause of ALI in Western countries, leading to around 26,000 hospitalizations and 500 deaths in the United States alone. 2 The metabolic activation of APAP through the CYP450 enzymes produces a toxic metabolite called N-acetyl-p-benzoquinone imine (NAPQI). One dose above the recommended maximum intake can increase production of NAPQI, with the subsequent generation of reactive oxygen species (ROS) and the formation of adducts in proteins and other biomolecules. Recent research into the etiology of NAPQI toxicity has focused on the mitochondrial damage and the depletion of mitochondrial glutathione (mGSH).Accumulated evidence shows that some populations are more susceptible to APAP-induced liver damage, including people with obesity, chronic alcohol consumption, viral hepatitis, acute and chronic malnutrition, and nonalcoholic fatty liver disease (NAFLD). Based on a preliminary observation that NAFLD increased the risk of ALI due to APAP overdose sevenfold, one retrospective study investigated the molecular mechanisms that increase the susceptibility of the steatotic hepatocytes to the APAP-induced cellular damage, even at a therapeutic dose. 3 Both murine and cell-based models have provided evidence that implicates the biotransformation of APAP to its toxic metabolite NAPQI in this process, through the cytochrome P450 family: CYP2E1, CYP3A4, CYP2D6, and CYP1A2. 4 Both NAPQI adducts and the detoxification process (in which GSH is used and depleted) have been re...

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Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

Cited by 101 publications

References 13 publications

Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

Biomarkers of Mitochondrial Injury After Acetaminophen Overdose

Acetaminophen‐Induced Liver Damage in Hepatic Steatosis

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