New insight into how paracetamol overdoses can damage liver

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Paracetamol overdose is the commonest cause of intentional drug overdose in Britain, with an estimated 70,000 cases each year. University of Dundee scientists have made a surprising new discovery into the way that paracetamol is metabolized in the liver. Their work highlights how an enzyme called GST Pi may moderate paracetamol's toxic effects. The research published this month in Proceedings of the National Academy of Sciences*, by Professor Roland Wolf and Dr Colin Henderson of Imperial Cancer Research Fund's Molecular Pharmacology Unit at the University of Dundee†, could lead to the development of novel treatments for cases of paracetamol overdose. Their findings also have implications for our understanding of how cancer cells may be sensitive to certain drugs and hence how we can design better drugs to treat cancer. Paracetamol is a commonly used painkiller, but when taken in overdose it can cause severe liver damage, often fatally. This damage is caused by NAPQI, a highly reactive substance formed during paracetamol metabolism by the cytochrome P450 system. Although NAPQI binds to cells causing damage and cell death, in low doses it is efficiently rendered safe by binding with a protein called glutathione instead. Previous laboratory studies appear to have shown that the enzyme GST Pi catalyses this reaction but in paracetamol overdoses the level of free glutathione is not enough to prevent toxic levels of NAPQI from accumulating. Professor Wolf, head of Molecular Pharmacology at the unit said: "We wanted to find out the exact mechanism that can make paracetamol toxic to cells. So we compared its metabolism in two groups of mice, one normal the other lacking the GST Pi enzyme. "The results were quite surprising and completely the opposite to our expectations. Rather than being more sensitive to the paracetamol, we discovered the mice without any GST Pi were much more resistant than normal ones. In both cases when paracetamol was given, free glutathione was quickly depleted. In normal mice this level remained low, leading to liver damage as the amount of NAPQI went unchecked. However in mice who didn't have any GST Pi the level of free glutathione actually recovered and the amount of liver damage was far less." Professor Wolf thinks this can be explained in a number of ways: "Firstly it's clear that GST Pi does not catalyze the conjugation of NAPQI and glutathione as previously thought, although it does play a novel role in paracetamol toxicity. We suggest that GST Pi may be interrupting a pathway that protects a cell against the stress of cytotoxic compounds. Therefore a lack of GST Pi would mean a cell would be less sensitive to toxic attack while the presence of GST Pi interferes with a cell's defences, making it more susceptible to paracetamol toxicity." Dr Colin Henderson commented on the significance of the research: "Of course we need to do more research to build on this, but this discovery offers the fresh possibility that in certain cases GST Pi inhibitors may protect against liver damage caused by paracetamol. This study doesn't just have implications for paracetamol overdoses, because GST Pi is found in nearly all normal cells and cancer cells, it looks like an important factor in cell sensitivity to toxic chemicals in general."/ends *Proceedings of the National Academy of Sciences, vol. 97, no.23, p12741-12745 The research was conducted in collaboration with Neil Kitteringham, Helen Powell and B. Kevin Park of the Department of Pharmacology and Therapeutics, University of Liverpool. Abbreviations:
NAPQI - N-acetyl-p-benzoquinoneimine
GST Pi- glutathione S-transferase Pi