TY  - UNPB
PB  - UCL (University College London)
A1  - Wong, Weng Sie
N1  - Thesis digitised by ProQuest.
N2  - 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.
UR  - https://discovery.ucl.ac.uk/id/eprint/10116697/
EP  - 278
ID  - discovery10116697
M1  - Doctoral
Y1  - 2000///
TI  - New aspects of the cellular effects of paracetamol and related antioxidants
AV  - public
ER  -