Keywords Biomarkers, Drugs, Multispecies assessment, Oxidative stress,
Painkillers
1 Introduction
Paracetamol is one of the most valued therapeutic responses in modern medicine,
given its analgesic properties, and its massive use as a painkiller started during the
1960s of the twentieth century [1]. Analgesics are a therapeutic class in which use
has been rising for the last decades, as shown by Diener et al. [2], and paracetamol is
among the most used pharmaceutical preparations used to treat and reduce pain of
different natures and origins. Retrospective data show that, among the most common
drugs consumed in developed countries, paracetamol is frequently among the top
five [3]. Consequently, paracetamol has been recently classified as a priority compound, whose toxicity characterization is urgently required [4]. In addition, paracetamol is often formulated in over-the-counter pharmaceutical preparations, a factor
that also contributes for its frequent use [5]. Considering its long history of use,
versatility, safety, and efficacy in common therapeutics, paracetamol is used by
millions of human patients, being of fundamental importance in pediatrics also
[6]. Despite this massive use, and quite paradoxically, paracetamol is frequently
associated both to unintentional poisoning and also to suicide among humans, due to
its severe toxicological effects when used in overdosage [7, 8]. In fact, recent
retrospective analysis about the concerns of users of this specific drug shows that
paracetamol effects are not entirely acknowledged and that a large amount of
questions on its safety still exist [9]. A long list of recent publications also shows
that paracetamol poisoning is a common subject in modern toxicology, as demonstrated by Zyoud et al. [10]. This reinforces the correct notion that despite being safe,
paracetamol is also toxic. In humans, paracetamol toxicity is usually evidenced with
the involvement of liver alterations, since the most frequently targeted locations for
the bioactive metabolites of this drug occur in the liver [1, 11–13]. Paracetamol
intoxication results in centrilobular hepatic necrosis [14], liver failure, and death.
Such outcomes are not restricted to humans, and similar effects were also reported to
occur in mammals ([15, 16]; Hadi et al. [17]), suggesting a similar (putatively
evolutionary conserved) mechanism of toxic action among a large number of
species.
Paracetamol has a number of features that are common to most non-steroid antiinflammatory drugs (NSAIDs), especially its mechanism of therapeutic action and
resulting effects. In fact, paracetamol seems to act by inhibiting the peroxidasic
activity of both cyclooxygenase forms (I and II), resulting in a significant impairment of prostaglandin biosynthesis, as summarized by Graham et al. [7]. However,
this is not the mechanism that is responsible for paracetamol’s toxicity. In fact,
paracetamol is prone to be promptly metabolized in normal, therapeutic dosages,
132
B. Nunes
Painkillers
1 Introduction
Paracetamol is one of the most valued therapeutic responses in modern medicine,
given its analgesic properties, and its massive use as a painkiller started during the
1960s of the twentieth century [1]. Analgesics are a therapeutic class in which use
has been rising for the last decades, as shown by Diener et al. [2], and paracetamol is
among the most used pharmaceutical preparations used to treat and reduce pain of
different natures and origins. Retrospective data show that, among the most common
drugs consumed in developed countries, paracetamol is frequently among the top
five [3]. Consequently, paracetamol has been recently classified as a priority compound, whose toxicity characterization is urgently required [4]. In addition, paracetamol is often formulated in over-the-counter pharmaceutical preparations, a factor
that also contributes for its frequent use [5]. Considering its long history of use,
versatility, safety, and efficacy in common therapeutics, paracetamol is used by
millions of human patients, being of fundamental importance in pediatrics also
[6]. Despite this massive use, and quite paradoxically, paracetamol is frequently
associated both to unintentional poisoning and also to suicide among humans, due to
its severe toxicological effects when used in overdosage [7, 8]. In fact, recent
retrospective analysis about the concerns of users of this specific drug shows that
paracetamol effects are not entirely acknowledged and that a large amount of
questions on its safety still exist [9]. A long list of recent publications also shows
that paracetamol poisoning is a common subject in modern toxicology, as demonstrated by Zyoud et al. [10]. This reinforces the correct notion that despite being safe,
paracetamol is also toxic. In humans, paracetamol toxicity is usually evidenced with
the involvement of liver alterations, since the most frequently targeted locations for
the bioactive metabolites of this drug occur in the liver [1, 11–13]. Paracetamol
intoxication results in centrilobular hepatic necrosis [14], liver failure, and death.
Such outcomes are not restricted to humans, and similar effects were also reported to
occur in mammals ([15, 16]; Hadi et al. [17]), suggesting a similar (putatively
evolutionary conserved) mechanism of toxic action among a large number of
species.
Paracetamol has a number of features that are common to most non-steroid antiinflammatory drugs (NSAIDs), especially its mechanism of therapeutic action and
resulting effects. In fact, paracetamol seems to act by inhibiting the peroxidasic
activity of both cyclooxygenase forms (I and II), resulting in a significant impairment of prostaglandin biosynthesis, as summarized by Graham et al. [7]. However,
this is not the mechanism that is responsible for paracetamol’s toxicity. In fact,
paracetamol is prone to be promptly metabolized in normal, therapeutic dosages,
132
B. Nunes