Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

doi:10.1016/j.phrs.2016.02.020

Pharmacological Research

Volume 109, July 2016, Pages 119-131

https://doi.org/10.1016/j.phrs.2016.02.020 Get rights and content

Abstract

Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe when administered within its therapeutic range, but in cases of acute intoxication, hepatotoxicity can occur. APAP overdose is the leading cause of acute liver failure in the northern hemisphere. Historically, studies on APAP toxicity have been focused on liver, with alterations in brain function attributed to secondary effects of acute liver failure. However, in the last decade the pharmacological mechanism of APAP as a cannabinoid system modulator has been documented and some articles have reported “in situ” toxicity by APAP in brain tissue at high doses. Paradoxically, low doses of APAP have been reported to produce the opposite, neuroprotective effects. In this paper we present a comprehensive, up-to-date overview of hepatic toxicity as well as a thorough review of both toxic and beneficial effects of APAP in brain.

Graphical abstract

Introduction

Acetaminophen (N-acetyl-para-aminophenol, paracetamol, APAP) was originally synthesized in 1878 by Morse [1] and first used clinically by von Mering in 1887 [2]. During that period, phenacetin was the most widely used analgesic in clinical practice. In the 1950s, the analgesic and antipyretic properties of APAP were re-discovered by Brodie and Axelrod [3] and they demonstrated that APAP was in fact the active metabolite of phenacetin. At that time, APAP was introduced in the U. S. market as a replacement drug for phenacetin, whose use was discontinued due to its nephrotoxic potential. Owing to its widespread acceptance as a safer alternative to phenacetin, APAP became one of the most popular and widely used over-the-counter analgesic-antipyretic drugs in the world, and the most commonly prescribed medication in children [4], [5]. Also, since the 1980’s APAP has become the first drug of choice for the treatment of pain and fever in children because of the high incidence of Reye’s syndrome associated with pediatric use of aspirin [6]. In the U.S., approximately 79% of the general population consume APAP regularly [7]. Many prescription and nonprescription formulations contain APAP alone or in combination with other drugs. Excessive self-medication is a prevalent practice responsible for many cases of APAP intoxicantion.

Section snippets

An update on the mechanism(s) of pharmacological action

Historically, APAP was initially categorized as a nonsteroidal anti-inflammatory drugs (NSADs). Multiple investigations compared its mechanism of action to that of classical NSAIDs, such as acetyl salicylic acid which inhibits the cyclooxygenase (COXs) pathway [8]. However, APAP was proven to be ineffective as an anti-inflammatory drug. It is well established that NSAIDs inhibit COX-dependent production of prostaglandins [9], while APAP largely lacks peripheral anti-inflammatory properties,

Incidence of hepatic toxicity

Although APAP was initially approved for clinical use in the 1950s, concerns about its safety did not become prominent until the 1970s. In the 1980s, APAP sales exceeded those of aspirin in many countries. Hepatotoxicity and liver failure by APAP intoxication were not recognized until the first cases of fatal APAP poisoning were reported in the mid-1980s.

According to the American Association for the Study of Liver Diseases, the incidence of APAP-related liver toxicity has been increasing

Hepatic metabolism and mechanism(s) of toxicity

Following therapeutic administration of APAP, approximately 25% of dose undergoes “first pass” metabolism, with the liver playing a primary role [37]. In the adult, APAP is mainly conjugated with glucuronic acid (40–67%) and sulphate (20–46%) [38], [39]. A minor fraction (5–15%) undergoes oxidative metabolism by CYP450, particularly the CYP2E1, CYP1A2, CYP3A4, and CYP2A6 isoforms. Such enzymatic reaction generates a reactive intermediate known as N-acetyl-p-benzoquinoneimine (NAPQI) [40] (Fig. 2

Therapeutic approaches to APAP toxicity

Currently, the only approved antidote for APAP toxicity is oral or intravenous administration of N acetyl-cysteine (NAC). This compound is a precursor in the synthesis of GSH. Therefore, its administration works in part by restoring the intracellular pool of GSH, and in part by neutralizing any residual NAPQI still present in the liver. This antidote therapy can be quite effective if administered within the first few hours after toxic APAP ingestion. This is not always the case since many

Paradoxical effects on the brain: protective vs toxic actions

As previously stated, APAP is a safe drug when administered at therapeutic doses. However, APAP overdosing is the most frequent cause of ALF in USA, England and many European countries [35]. During progression of ALF, the appearance of hepatic encephalopathy (HE) is indicative of worsening liver function.

Usually, the HE syndrome produces neuropsychiatric symptoms which manifest themselves from mild to severe, with coma as the ultimate sequelae. HE is characterized by the presence of brain edema

Conclusion

In summary, while hepatic toxicity by APAP has been extensively studied, the direct toxic effect of APAP in the brain has been received less attention. It is known that high doses of APAP promotes oxidative stress and produces damage to different cell types in the brain. But the structural and functional consequences of these effects is still unknown. This should be the subject of further investigations to clearly discriminate between liver-driven vs true in situ adverse effects of APAP in

Acknowledgements

This work was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica (PICT 2012-1753 and PICT 2014-0476) to Carolina I. Ghanem and Aldo D. Mottino respectively, and by a grant from National Institutes of Health (DK069557) to José E. Manautou.

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ReviewAcetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

Abstract

Graphical abstract

Introduction

Section snippets

An update on the mechanism(s) of pharmacological action

Incidence of hepatic toxicity

Hepatic metabolism and mechanism(s) of toxicity

Therapeutic approaches to APAP toxicity

Paradoxical effects on the brain: protective vs toxic actions

Conclusion

Acknowledgements

Toxicology

Microvasc. Res.

Eur. J. Pharmacol.

J. Biol. Chem.

Trends Neurosci.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Neuropharmacology

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

J. Biol. Chem.

Toxicol. Lett.

Toxicology

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

Biochem. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Gastroenterology

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Lett.

Immunity

FEBS Open. Bio

J. Hepatol.

Gastroenterology

Adv. Pharmacol.

Pharmacol. Res.

Ueber eine neue Darstellungsmethode der Acetylamidophenole

Ber Deutscher Chem. Ges

Beitrage zur Kenntniss der Antipyretica

Ther. Monatsch.

The fate of acetanilide in man

J. Pharmacol. Exp. Ther.

Trends in prescriptions of paracetamol for children

BMJ

A literature review on off-label drug use in children

Eur. J. Pediatr.

Paracetamol efficacy and safety in children: the first 40 years

Am. J. Ther.

Patterns of use and public perception of over-the-counter pain relievers: focus on nonsteroidal antiinflammatory drugs

J. Rheumatol.

Paracetamol: new vistas of an old drug

CNS Drug Rev.

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

Nat. New Biol.

Acetaminophen distribution in the rat central nervous system

Life Sci.

Paracetamol (acetaminophen) penetrates readily into the cerebrospinal fluid of children after intravenous administration

Pediatrics

Uptake of paracetamol into brain and liver of rats

Bangladesh Med. Res. Counc. Bull.

Levels of acetaminophen and its metabolites in mouse tissues after a toxic Dose

J. Pharmacol. Exp. Ther.

Review
Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity