Wong, Weng Sie; (2000) New aspects of the cellular effects of paracetamol and related antioxidants. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In order to further understand the cellular effects of paracetamol and other related antioxidants, two different aspects have been studied; (i) Inhibition of DNA synthesis by paracetamol and related antioxidants. Paracetamol is known to have antioxidant and radical scavenging properties and it has been recently observed that paracetamol inhibits DNA synthesis through inhibition of ribonucleotide reductase. This property is similar to that of hydroxyurea, a well known DNA synthesis inhibitor which also inhibits ribonucleotide reductase activity by destroying the tyrosyl free radical. An objective of the present study is to determine whether paracetamol concentrations found in human therapeutic use or overdose are likely to inhibit DNA synthesis in humans. Other antioxidants were also included to broaden the scope of the investigations since it seems likely that any antioxidant which has the right shape and size to inhibit ribonucleotide reductase will inhibit DNA synthesis. Tissues (testis, spleen and liver) from male Wistar rats were used in an ir? vitro tissue slice system to study the concentration-response relationships for inhibition of DNA synthesis by different compounds. Inhibition of protein synthesis was used as a control to assess non-specific cell damage. Paracetamol and hydroxyurea were found to inhibit DNA synthesis in a dosedependent manner in vitro, with little effect on protein synthesis. Considerable variation in the sensitivity of the different tissues was also observed with an order of most sensitive to least sensitive tissue of spleen > testis > liver. Some other phenolic antioxidants have also been found to inhibit DNA synthesis specifically but this was not a property shared by all phenolic antioxidants. (ii) Role o f apoptosis pathways in paracetamol-induced liver cell injury. Previous studies have suggested that paracetamol can cause apoptotic changes. An objective of the present study is to determine whether apoptotic pathways are involved in the hepatotoxic effects of paracetamol. A dose-response and a time course study were conducted with groups of male C57B1/6 mice and necrotic and apoptotic cell injury assessed. Necrotic cell injury was assessed at the microscopic level (H&E) and the degree of damage was correlated with plasma alanine aminotransferase (ALT) levels. Apoptotic changes were investigated using the TUNEL method in liver sections, Western blot analysis for poly (ADP-ribose) polymerase (PAR?) cleavage in liver protein lysates and immunohistochemical staining for Bax protein expression in liver sections. Essentially no evidence was found for the involvement of apoptotic pathways in liver cell injury due to paracetamol overdose.

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