Waterfield, Catherine Jane; (1992) The influence of foreign compounds on taurine levels: an in vivo and in vitro study. Doctoral thesis (Ph.D.), University College London.

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Abstract

Abstract The studies described in this thesis examine the possibility of using changes in levels of urinary taurine as non-invasive markers of liver dysfunction in rats and humans. The hepatotoxic compounds carbon tetrachloride (CC14), thioacetamide, allyl alcohol and galactosamine caused elevations of urinary taurine in rats, at doses which induced liver necrosis. The elevations were correlated with increases in serum transaminase enzymes. However, hydrazine and ethionine administration also increased urinary taurine but neither of these compounds resulted in liver necrosis nor raised serum transam inase enzymes. Conversely, the glutathione depleting hepatotoxic compound bromobenzene, produced liver necrosis but no hypertaurinuria and anapthylisothiocyanate resulted in cholestasis and caused a significant hypotaurinuria. The non-hepatotoxic compounds mercuric chloride and allylamine failed to raise urinary taurine and cadmium chloride only caused slight hypertaurinuria in those animals which developed hepatic steatosis. Urinary taurine in humans suffering from alcoholic liver disease was significantly raised and was correlated with elevated serum AST and reduced total plasma protein levels. Other studies demonstrated that urinary creatine was raised by the hepatotoxic compounds CC14, thioacetamide and bromobenzene. Perturbation of protein synthesis in rats, by treatm ent with cycloheximide or of glutathione levels by treatm ent of rats with diethyl maleate, phorone or buthionine sulphoximine, also altered urinary taurine profiles. This suggests that hypertaurinuria is probably enhanced by compounds which inhibit protein and glutathione synthesis and is reduced by compounds which conjugate with glutathione. The contribution made by de novo taurine synthesis to CCl4-induced hypertaurinuria in rats was investigated using 3 5S-methionine and 3H-taurine. Results suggested th at the initial hypertaurinuria resulting from CC14 administration (0-24 h post-dose) was due to leaked cellular taurine and that an increase in taurine synthesis contributed to the hypertaurinuria measured 24-48 h after dosing. The appearance of taurine in the incubation media of isolated rat hepatocytes was an early sign of toxicity and taurine synthesis appeared to be increased in isolated rat hepatocytes challenged with a sub-toxic concentration of CC14. It was also shown that, in control rats, low levels of taurine in the liver were correlated with low urinary taurine. Animals with low urinary taurine, dosed with CC14, subsequently developed a greater elevation of serum transam inase enzymes than rats with higher levels of urinary taurine. Depletion of liver taurine with administration of (3-alanine also resulted in enhanced CC14 toxicity. Taurine provided some protection for isolated hepatocytes against CC14 and hydrazine toxicity. These investigations suggest th at (a) measurement of urinary taurine could be a useful non-invasive tool for the detection of (i) metabolic perturbations in the liver (ii) direct liver damage by hepatotoxic compounds and (iii) compounds which interfere with protein synthesis (b) lowered levels of taurine in the liver may result in increased toxicity of hepatotoxic compounds (c) taurine may be a useful marker of cytotoxicity in hepatocytes and (d) taurine is cytoprotective, both in vivo and in vitro.

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