Kerai, Mita; (1999) The role of taurine in the susceptibility to hepatotoxic compounds: studies on hydrazine, paracetamol and ethanol. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Taurine is the major free intracellular β-amino acid, present in high concentrations in many tissues of man and animals. The studies reported in this thesis, investigate the possible role of taurine in protecting against hydrazine, paracetamol and ethanol induced hepatic dysfunction, both in vivo and in vitro in isolated hepatocytes. Urinary taurine was found to be a non-invasive marker of acute hydrazine induced hepatic steatosis in rats (depending on the extent of hepatic damage), acute paracetamol induced hepatic necrosis in hamsters, but not chronic ethanol induced hepatic steatosis in rats. Hydrazine and paracetamol caused hepatic steatosis and hepatic necrosis, respectively in rats and hamsters. Some biochemical parameters indicated that there may have been: a) an increase in the hepatotoxicity of paracetamol following treatment of hamsters with β-alanine, which lowered tissue taurine levels, and b) protection by taurine administration, on the basis of changes observed in urinary parameters. These observations could not be confirmed histologically, however. The co-administration of taurine and alcohol chronically to rats, and administration of taurine for 2 days following chronic alcohol administration, significantly decreased both the fatty liver and hepatic lipid peroxidation produced by alcohol. The activity of the ethanol inducible cytochrome P-450 2E1 (CYP2E1) was significantly decreased by taurine when co-administered with alcohol. As many hepatotoxic compounds are known to be metabolised and undergo metabolic activation by CYP2E1, this effect was recognised to be potentially of great importance. As taurine treatment appeared to reduce hepatic triglyceride levels and increase serum triglycerides, it was suggested that taurine may have stimulated the rate of triglyceride export from the liver. In animals depleted of hepatic and serum taurine by co-administration of ?-alanine with alcohol, the susceptibility to ethanol induced hepatic steatosis, as assessed histologically was increased. Changes in methionine metabolism in the liver may have an important role in alcohol toxicity, as methionine is important in phosphatidylcholine synthesis, which forms lipoproteins that transport fat out of cells. Ethanol administration was found to inhibit hepatic methionine synthase activity in vivo , which is consistent with the raised levels of homocysteine detected in the urine, and may offer another explanation for the alcohol induced fatty liver.

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