Hepatotoxin-induced hypertyrosinemia and its toxicological significance
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A 1H Nuclear Magnetic Resonance (NMR) spectroscopic investigation of the effects of single doses of four model hepatotoxins on male Sprague–Dawley rats showed that hypertyrosinemia was induced by three of the treatments (ethionine 300 mg/kg, galactosamine hydrochloride 800 mg/kg and isoniazid 400 mg/kg) but not by the fourth (thioacetamide 200 mg/kg). Concomitant histopathological and clinical chemistry analyses showed that hypertyrosinemia could occur with or without substantial hepatic damage and that substantial hepatic damage could occur without hypertyrosinemia. However, in the rats dosed with galactosamine hydrochloride, which showed highly variable amounts of liver damage at ca. 24 h after dosing, a clear relationship was found between the degree of hypertyrosinemia and the extent of the hepatic necrosis induced. In line with the cause of clinically observed Type II Tyrosinemia, we consider that the critical event in the onset of hepatotoxin-induced hypertyrosinemia is likely to be a reduction in hepatic tyrosine aminotransferase (TAT) activity. We discuss mechanisms by which TAT activity could be lost with special consideration given to pyridoxal 5′-phosphate (P5P) depletion and to the inhibition of protein synthesis. This analysis may have implications for the interpretation of clinical measures of liver status such as Fischer’s ratio and the branched-chain tyrosine ratio (BTR).
KeywordsEthionine Galactosamine Isoniazid Thioacetamide Liver Hypertyrosinemia Tyrosine Aminotransferase Rat
The authors gratefully acknowledge the assistance of Brigitte Geffray, Pfizer Global R&D, Amboise (statistical analysis), the technical staff of Pfizer Global R&D, Amboise (animal work) the facilities and assistance provided by the ULIRS NMR Service at Queen Mary and Westfield College, London and the financial support of Pfizer Global R&D to T.A.C. All of the experiments performed complied with the relevant national legislation.
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