without the establishment of any toxic effect. Low levels of paracetamol end up
usually in its conjugation, namely, by sulfation and also glucuronidation [11, 18,
19], resulting in water-soluble intermediates whose presence in the organism is
short, being excreted. A small portion of the administered paracetamol is metabolized by hepatic cells via the oxidative pathway with the involvement of cytochrome
P450 (especially CYP2E1 and CYP1A2), as described by [20]. This portion of
paracetamol is then bioactivated, giving rise to a highly reactive intermediate,
designated N-acetyl-p-benzoquinone imine (NAPQI). NAPQI, despite its reactivity,
may be conjugated with glutathione, with the involvement of the isoenzymes
glutathione S-transferases, being then excreted as cysteine or mercapturic acid
[21]. However, all the described conjugation pathways may be exhausted if the
ingested amount of paracetamol exceeds the conjugation capacity, i.e., the intracellular available amount of each cofactor. At toxic doses, the sulfate, glucuronic acid,
and reduced glutathione pools are depleted, and NAPQI accumulates resulting in
toxicity. Being metabolized and bioactivated mostly in the liver, NAPQI concentration in this organ increases, impairing the biosynthesis of ATP, triggering DNA and
RNA damages and binding to proteins and subcellular structures, thereby inducing
rapid cell death and necrosis [22]. NAPQI accumulation is also responsible for an
excessive accumulation of intracellular peroxide (due to glutathione depletion), a
main factor that is the basis of damages by reactive species of oxygen (ROS) via
Fenton mechanism, causing oxidative stress and extensive lipid peroxidation of
cellular membranes [1, 23, 24]. Considering that the metabolic pathways involved
both in the metabolism and in the bioactivation of paracetamol are evolutionary
conserved, it is expectable that the previously described toxicity features may also
occur in a large number of organisms, namely, those that are exposed via the
environment. In addition, oxidative stress may result in the establishment of adverse
effects as a consequence of the denaturation of specific proteins by ROS, as shown to
occur in several mollusk, crustacean, and fish species. These effects included
deleterious modifications in enzymes such as cholinesterases, with significant behavioral alterations, as evidenced in Phorcus lineatus [25], Daphnia magna [26],
Anguilla anguilla [27], and Phalloceros harpagos [28]. The importance of the causal
relationship between oxidative stress and cholinesterasic inhibition is ecologically
significant. Since it shows that some compounds may alter behavioral traits by
modulating redox imbalances and not by acting directly on the nervous system of
exposed organisms. In turn, behavioral disturbances may be held accountable for
loss of common responses, including reflexes (escape, sexual interaction, aggression, camouflage) that are determinant for the survival of species and for the
ecological balance.
1.1 Environmental Presence and Fate of Paracetamol
Given its massive use, paracetamol is released into sewage systems by human
patients, a factor that justifies its frequent detection in wastewater [29–31]. Despite
Ecotoxicological Effects of the Drug Paracetamol: A Critical Review of Past. . .
133
usually in its conjugation, namely, by sulfation and also glucuronidation [11, 18,
19], resulting in water-soluble intermediates whose presence in the organism is
short, being excreted. A small portion of the administered paracetamol is metabolized by hepatic cells via the oxidative pathway with the involvement of cytochrome
P450 (especially CYP2E1 and CYP1A2), as described by [20]. This portion of
paracetamol is then bioactivated, giving rise to a highly reactive intermediate,
designated N-acetyl-p-benzoquinone imine (NAPQI). NAPQI, despite its reactivity,
may be conjugated with glutathione, with the involvement of the isoenzymes
glutathione S-transferases, being then excreted as cysteine or mercapturic acid
[21]. However, all the described conjugation pathways may be exhausted if the
ingested amount of paracetamol exceeds the conjugation capacity, i.e., the intracellular available amount of each cofactor. At toxic doses, the sulfate, glucuronic acid,
and reduced glutathione pools are depleted, and NAPQI accumulates resulting in
toxicity. Being metabolized and bioactivated mostly in the liver, NAPQI concentration in this organ increases, impairing the biosynthesis of ATP, triggering DNA and
RNA damages and binding to proteins and subcellular structures, thereby inducing
rapid cell death and necrosis [22]. NAPQI accumulation is also responsible for an
excessive accumulation of intracellular peroxide (due to glutathione depletion), a
main factor that is the basis of damages by reactive species of oxygen (ROS) via
Fenton mechanism, causing oxidative stress and extensive lipid peroxidation of
cellular membranes [1, 23, 24]. Considering that the metabolic pathways involved
both in the metabolism and in the bioactivation of paracetamol are evolutionary
conserved, it is expectable that the previously described toxicity features may also
occur in a large number of organisms, namely, those that are exposed via the
environment. In addition, oxidative stress may result in the establishment of adverse
effects as a consequence of the denaturation of specific proteins by ROS, as shown to
occur in several mollusk, crustacean, and fish species. These effects included
deleterious modifications in enzymes such as cholinesterases, with significant behavioral alterations, as evidenced in Phorcus lineatus [25], Daphnia magna [26],
Anguilla anguilla [27], and Phalloceros harpagos [28]. The importance of the causal
relationship between oxidative stress and cholinesterasic inhibition is ecologically
significant. Since it shows that some compounds may alter behavioral traits by
modulating redox imbalances and not by acting directly on the nervous system of
exposed organisms. In turn, behavioral disturbances may be held accountable for
loss of common responses, including reflexes (escape, sexual interaction, aggression, camouflage) that are determinant for the survival of species and for the
ecological balance.
1.1 Environmental Presence and Fate of Paracetamol
Given its massive use, paracetamol is released into sewage systems by human
patients, a factor that justifies its frequent detection in wastewater [29–31]. Despite
Ecotoxicological Effects of the Drug Paracetamol: A Critical Review of Past. . .
133