Abstract
The aim of the work presented in this thesis was to assess the protective properties of the bioflavanoid drug, (+)-catechin, and its palmityl ester, 3-palmitoyl-(+)-catechin, against ethanol hepato-toxicity (ie: fatty liver) in the rat. In initial experiments, both (+)-catechin compounds were found to protect against the hepatic lipid accumulation (mainly triglyceride) after acute ethanol dosing, and after long-term feeding of ethanol in a liquid diet. In the latter situation, 3-palmitoyl-(+)-catechin was significantly more effective than (+)-catechin itself at preventing fatty liver, probably as a result of its greater lipid solubility and longer half-life in the liver tissue. Published work suggested two possible mechanisms of action for the (+)-catechin compounds against ethanol hepatotoxicity. Firstly, the ability of the drugs to correct the elevated hepatic NADH:NAD ratio (redox-state) after ethanol dosing may limit steatosis. Secondly, free radical scavenging properties may prevent liver injury occurring as a result of ethanol-induced lipid peroxidation. Acute experiments were performed which confirmed that the (+)-catechin compounds corrected the redox-state change after acute ethanol administration, but subsequent studies in which correction of the redox-state by Naloxone or Methylene Blue was found to have little influence on ethanol-induced steatosis, suggested that this was not the mechanism of action of the drugs. Synthetic antioxidants (free radical scavengers) were found to prevent both acute and chronic ethanol-induced fatty liver, under the same experimental conditions as those under which the (+)-catechin compounds afforded protection, without reversing the redox-state change after ethanol dosing. 3-Palmitoyl-(+)-catechin was then shown to prevent ethanol-induced hepatic lipid peroxidation (measured as mitochondrial diene conjugates and liver malonaldehyde levels) after acute ethanol dosing, at the same time as preventing triglyceride accumulation. As other effects of the compounds which might influence fat accumulation after ethanol were excluded (eg: inhibition of ethanol metabolism or lowering of liver acetaldehyde concentrations), it was concluded that the (+)-catechin compounds protect against alcoholic fatty liver in rats by inhibiting ethanol-induced lipid peroxidation, and the possible consequence of the latter (ie: mitochondrial damage and impaired fatty acid oxidation), rather than acting through modulation of the redox-state. The findings here cast doubts on the commonly-quoted 'redox-state' mechanism for fatty liver production by ethanol, and support the lipid peroxidation hypothesis for alcoholic liver injury.