Hepatotoxicity due to repeated intake of low doses of paracetamol

Eriksson, L. S.; Broomé, Ulrika; Kalin, Mats; Lindholm, Marianne

doi:10.1111/j.1365-2796.1992.tb00976.x

Cited by 84 publications

(54 citation statements)

References 15 publications

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“…Paracetamol is a common antipyretic agent, which is safe in therapeutic doses but can produce fatal hepatic necrosis in man, rats and mice with toxic doses [23][24][25] . Protection against paracetamol-induced toxicity has been used as a test for potential hepatoprotective activity by several investigations [26][27][28][29][30] .…”

Section: Resultsmentioning

confidence: 99%

Hepatoprotective Activity of Aqueous Ethanolic Extract of Chamomile capitula in Paracetamol Intoxicated Albino Rats

Gupta¹,

Misra²

2006

American J. of Pharmacology and Toxicology

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Hepatoprotective activity of aqueous ethanolic extract of Chamomile recutita capitula against paracetamol induced hepatic damage in albino rats was observed. In the present study the effect of aqueous ethanolic extract of Chamomile recutita capitula on blood and liver glutathione, Na + K + -ATPase activity, serum marker enzymes, serum bilirubin, glycogen and thiobarbutiric acid reactive substances against paracetamol induced damage in rats have been studied to find out the possible mechanism of hepatoprotection. It was observed that extract of chamomile has reversal effects on the levels of above-mentioned parameters in paracetamol hepatotoxicity. The extract of capitula of chamomile functions as a hepatoprotective agent and this hepatoprotective activity of chamomile may be due normalization of impaired membrane function activity.

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Section: Resultsmentioning

confidence: 99%

Hepatoprotective Activity of Aqueous Ethanolic Extract of Chamomile capitula in Paracetamol Intoxicated Albino Rats

Gupta¹,

Misra²

2006

American J. of Pharmacology and Toxicology

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“…The development of this assay provides a tool for the systematic study of APAP toxicity in humans following toxic exposures or therapeutic misadventures with APAP. Recent literature has highlighted the occurrence of therapeutic misadventures with APAP (Seeff et al, 1986;Eriksson et al, 1992;Bonkovsky et al, 1994;Whitcomb and Block, 1994;Rivera-Penera et al, 1997;Heubi et al, 1998). These articles describe the development of hepatotoxicity in patients using APAP with therapeutic intent.…”

Section: Discussionmentioning

confidence: 99%

Determination of Acetaminophen-Protein Adducts in Mouse Liver and Serum and Human Serum after Hepatotoxic Doses of Acetaminophen Using High-Performance Liquid Chromatography with Electrochemical Detection

Muldrew¹,

James²,

Coop³

et al. 2002

Drug Metab Dispos

181

174

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Acetaminophen-induced hepatotoxicity has been attributed to covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to cysteine groups on proteins as an acetaminophen-cysteine conjugate. We report a high-performance liquid chromatography with electrochemical detection (HPLC-ECD) assay for the conjugate with increased sensitivity compared with previous methods. Previous methods to quantitate the protein-bound conjugate have used a competitive immunoassay or radiolabeled acetaminophen. With HPLC-ECD, the protein samples are dialyzed and then digested with protease. The acetaminophen-cysteine conjugate is then quantified by HPLC-ECD using tyrosine as an internal reference. The lower limit of detection of the assay is approximately 3 pmol/mg of protein. Acetaminophen protein adducts were detected in liver and serum as early as 15 min after hepatotoxic dosing of acetaminophen to mice. Adducts were also detected in the serum of acetaminophen overdose patients. Analysis of human serum samples for the acetaminophen-cysteine conjugate revealed a positive correlation between acetaminophen-cysteine conjugate concentration and serum aspartate aminotransferase (AST) activity or time. Adducts were detected in the serum of patients even with relatively mild liver injury, as measured by AST and alanine aminotransferase. This assay may be useful in the diagnostic evaluation of patients with hepatotoxicity of an indeterminate etiology for which acetaminophen toxicity is suspect.Acetaminophen (N-acetyl-p-aminophenol; APAP 1 ; Paracetamol) is the most commonly used drug for the treatment of pain and fever. Although safe at therapeutic doses, in overdose, acetaminophen produces severe hepatotoxicity. The mechanism of toxicity is by initial metabolism to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome P450 . At therapeutic doses, the reactive metabolite is detoxified by glutathione, but following overdoses, glutathione is depleted and the metabolite covalently binds to proteins as 3-(cystein-S-yl)-acetaminophen (APAP-CYS) (Streeter et al., 1984). Covalent binding to protein is thought to be a critical step in the development of hepatotoxicity.A number of methods have been used to quantify the amount of acetaminophen covalently bound to proteins. In initial studies showing the correlation between acetaminophen toxicity and covalent binding, Jollow and coworkers (1973) used radiolabeled acetaminophen. Subsequently, polyclonal antisera were raised that recognized the acetaminophen-cysteine adducts (Bartolone et al., 1987;Roberts et al., 1987), and the relationship between covalent binding and toxicity was studied extensively. coworkers (1989, 1990) developed a competitive enzyme-linked immunosorbent assay to quantify acetaminophen covalent binding in the liver and serum of treated mice. In addition, Western blot assays were performed. Although these latter assays were not quantitative, they were useful in comparing t...

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“…These are generally categorized as either conditions that increase the production of the reactive metabolite NAPQI or that decrease the ability to detoxify NAPQI (e.g., decreased concentration of glutathione). Authors report that low daily doses of acetaminophen, ranging from minimal daily doses of 2.4-6 g in alcoholics, patients with starvation, or those on chronic antituberculous medications have been associated with elevated aminotransferase levels (40,(64)(65)(66). Case reports (level 4), case series (level 4), and cohort (level 2b) or case-control (level 3b) studies have reported either greater severity of injury or a lower threshold dose for the development of hepatotoxicity after acetaminophen ingestion by patients chronically ingesting alcohol or other compounds thought to increase susceptibility to acetaminophen toxicity (e.g., isoniazid use, prolonged fasting) (2,34,(36)(37)(38)40,41,46,50,65,(67)(68)(69)(70)(71)(72).…”

Section: Repeated Supratherapeutic Ingestion (Rsti) By Patients 6 Yeamentioning

confidence: 99%

Acetaminophen Poisoning: an Evidence-Based Consensus Guideline for Out-of-Hospital Management

Dart

Erdman

Olson

et al. 2006

Clinical Toxicology

131

102

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The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of acetaminophen. An evidencebased expert consensus process was used to create this guideline. This guideline applies to ingestion of acetaminophen alone and is based on an assessment of current scientific and clinical information.

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Hepatotoxicity due to repeated intake of low doses of paracetamol

Cited by 84 publications

References 15 publications

Hepatoprotective Activity of Aqueous Ethanolic Extract of Chamomile capitula in Paracetamol Intoxicated Albino Rats

Hepatoprotective Activity of Aqueous Ethanolic Extract of Chamomile capitula in Paracetamol Intoxicated Albino Rats

Determination of Acetaminophen-Protein Adducts in Mouse Liver and Serum and Human Serum after Hepatotoxic Doses of Acetaminophen Using High-Performance Liquid Chromatography with Electrochemical Detection

Acetaminophen Poisoning: an Evidence-Based Consensus Guideline for Out-of-Hospital Management

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