An Example of a Drug That Causes Toxicity Through the Formation of a Chemically Reactive Intermediate

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Chapter: Pharmacovigilance: Mechanisms of Adverse Drug Reactions

TYPE B OR IDIOSYNCRATIC ADVERSE DRUG REACTIONS : Paracetamol: An Example of a Drug That Causes Toxicity Through the Formation of a Chemically Reactive Intermediate


For many drugs that undergo metabolism, CRM will be formed irrespective of the dose of the drug (Pirmohamed, Madden and Park, 1996). When a drug is taken in therapeutic dosage, any toxic metabo-lite formed will be detoxified by normal enzymatic or non-enzymatic cellular defence mechanisms. An imbalance between bioactivation and bioinactivation leading to toxicity may however be created by taking a drug overdose. This will lead to the formation of large amounts of CRM, overwhelm the cellular detoxication capacity and lead to cell damage. The clearest exam-ple of this is paracetamol, which causes hepatotoxicity when taken in overdosage, and still causes about 160 deaths per year in the United Kingdom (Bray, 1993). According to the conventional definition of ADRs, paracetamol hepatotoxicity should not be classified as an ADR, because the hepatic injury occurs when the drug is used inappropriately. However, it is impor-tant to note that the occurrence of liver damage with paracetamol and its severity is a function not only of the dose but also of various host factors (Pirmohamed, Kitteringham and Park). Indeed, paracetamol hepato-toxicity has been reported with therapeutic drug use. For example, a recent study in 67 alcoholics who had sustained liver injury after paracetamol ingestion showed that 40% had taken less than 4 g/day (the maximum recommended therapeutic dose), whereas another 20% had taken between 4 and 6 g/day (which is also regarded as a non-toxic dose) (Zimmerman and Maddrey, 1995).

In therapeutic dosage, paracetamol is largely metabolised by phase II processes (glucuronidation and sulphation) to stable metabolites, but between 5% and 10% also undergoes P450 metabolism to the toxic N -acetyl p-benzoquinoneimine (NAPQI) metabolite (Nelson, 1990) (Figure 8.3). This is detox-ified by cellular glutathione. In overdosage, satura-tion of the phase II metabolic pathways results in a greater proportion of the drug undergoing bioactiva-tion. This ultimately leads to the depletion of cellular glutathione and allows the toxic metabolite to bind to hepatic proteins resulting in hepatocellular damage (Nelson, 1990). The use of N -acetylcysteine in the treatment of paracetamol overdosage illustrates the important point that elucidation of the mechanism of drug toxicity can lead to the development of ratio-nal therapies that will prevent the toxicity. Alcoholics show increased susceptibility to paracetamol over-dosage because excess alcohol consumption results in the depletion of glutathione (Lauterburg and Velez, 1988) and induction of the P450 isoform CYP2E1 (Raucy et al., 1989). Recent studies in knockout mice have shown that CYP2E1 is the primary isoform involved in the bioactivation of paracetamol (Lee et al., 1996).

Although experiments with transgenic mice have shown that in the absence of phase I oxidative pathways and therefore NAPQI formation, hepato-toxicity does not occur, the precise pathway lead-ing to liver damage is still unclear (Gibson et al., 1996). Several mechanisms have been proposed, including effects on plasma membrane Ca2+ pumps (Tsokos-Kuhn, 1989), which can lead to Ca2+-induced DNA damage (Ray et al., 1990), mito-chondrial damage (Meyers et al., 1988) resulting in glutathione depletion and oxidative stress (Jaeschke, 1990) and apoptosis (Ray et al., 1996). Recently, it has been shown that Fas antisense oligonucleotide protects mice from paracetamol toxicity, suggest-ing that the ultimate cytotoxic event involves more than simply necrosis and that cells of the immune system may be recruited in the inflammatory response (Zhang et al., 2000). Interestingly, several studies have revealed that cells exposed to chemical or oxidant stress will respond with an orchestrated and robust transcriptional response aimed at detoxify-ing the offending chemical and preventing or repair-ing cellular damage (Hayes et al., 1999; Moinova and Mulcahy, 1998, 1999). If unsuccessful, then the culmination of this response, known as the antiox-idant response, is to commit the cell to suicide through apoptosis. The target genes for the antioxidant response encode a set of enzymes and other proteins that scavenge free radicals, neutralise electrophiles or up-regulate the critical cellular thiol, glutathione. Glutathione depletion caused by a range of chemicals leads to the up-regulation of c-jun and c-fos mRNA and enhances activator protein-1 (AP-1) DNA bind-ing activity (Kitteringham et al., 2000). This response was also accompanied by the induction of -glutamyl cysteine synthetase (GCS). Another important mech-anism of cell protection involves the nuclear translo-cation of redox-sensitive transcription factors such as Nrf-2, which ‘sense’ chemical danger and orches-trate cell defence. Importantly, it has been observed that nuclear translocation occurs at non-toxic doses of paracetamol and at time points before overt toxi-city is observed. However, with increasing doses of acetaminophen, there is progressive dislocation of nuclear translocation, transcription, translation and protein activity as the rate of drug bioactivation over-whelms cell defence through the destruction of crit-ical proteins – at least 31 of these critical proteins have been identified (Park et al., 2005).

Paradoxically, studies performed with transgenic mice aimed at clarifying events subsequent to NAPQI formation have only served to confound rather than to clarify. For example, the deletion of compo-nents of the glutathione detoxication system such as glutathione peroxidase (Mirochnitchenko et al., 1999) and glutathione transferase-pi (GST-pi) (Henderson et al., 2000) both afforded partial protection against paracetamol hepatotoxicity. The loss of a major hepatic form of GST, which represents over 3% of total soluble protein (Fountoulakis et al., 2000), would have been expected to predispose the animals to hepa-totoxicity through a reduction in the glutathione conju-gation of NAPQI (Coles et al., 1988). This suggests that GST-pi may be involved in a novel mechanism that determines susceptibility to paracetamol hepato-toxicity. Indeed, a recent study has shown that GST-pi may have a role in cell signaling; it has been shown to be an efficient inhibitor of Jun kinase (also known as stress-activated kinase), the enzyme that activates c-jun and several other transcription factors (Adler et al., 1999). Future studies using other transgenic mouse models will be useful in determining the exact path-way by which paracetamol causes liver damage and may therefore provide novel therapeutic strategies by which to reverse liver damage in patients who present late after paracetamol overdosage.

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