Figure 6.3. The role of metabolism in the hepatotoxicity associated with paracetamol.
leading 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), mitochondrial 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, suggesting 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 detoxifying the offending chemical and preventing or repairing cellular damage (Hayes et al., 1999; Moinova and Mulcahy, 1998, 1999). If unsuccessful, the culmination of this response, known as the antioxidant 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, neutralize electrophiles, or up-regulate the critical cellular thiol, glutathione. Glutathione depletion caused by a range of chemicals leads to up-regulation of c-jun and c-fos mRNA, and enhances AP-1 DNA binding activity (Kitteringham et al., 2000). This response was also accompanied by induction of 7-glutamyl cysteine synthetase (GCS). What was surprising for paracetamol, in contrast to the other compounds, was that despite the increased GCS protein levels, catalytic activity was in fact reduced. This finding, which presumably involves a post-translational modification of the protein, may contribute to the inability of hepatocytes to defend themselves against paracetamol, whilst recovery from other compounds that deplete glutathione to the same extent can be achieved through enhanced synthetic activity.
Paradoxically, studies performed with trans-genic mice aimed at clarifying events subsequent to NAPQI formation have only served to confound rather than to clarify. For example, deletion of components of the glutathione detoxication system such as glutathione peroxidase (Miroch-nitchenko et al., 1999) and glutathione transferase 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 hepatotoxi-city through a reduction in the glutathione conjugation of NAPQI (Coles et al., 1988). This suggests that GST-pi may be involved in a novel mechanism that determines susceptibility to paracetamol hepatotoxicity. Indeed, a recent study has shown that GST-pi may have a role in cell signalling; 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 mice models will be useful in determining the exact pathway 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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