%0 Thesis
%9 Doctoral
%A Wong, Weng Sie
%D 2000
%F discovery:10116697
%I UCL (University College London)
%P 278
%T New aspects of the cellular effects of paracetamol and related antioxidants
%U https://discovery.ucl.ac.uk/id/eprint/10116697/
%X 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.
%Z Thesis digitised by ProQuest.