Hepatotoxin-induced hypertyrosinemia and its toxicological significance.

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Clayton TA, Lindon JC, Everett JR, Charuel C, Hanton G, Le Net JL, Provost JP, Nicholson JK

Hepatotoxin-induced hypertyrosinemia and its toxicological significance.

Arch Toxicol. 2007 Mar;81(3):201-10. Epub 2006 Aug 11.

PubMed ID

16902803 [ View in PubMed

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Abstract

A (1)H 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).

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pyridoxal phosphate	Tyrosine aminotransferase	Protein	Humans	Unknown	Cofactor	Details