Abstract
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).
Similar content being viewed by others
References
Anthony ML, Sweatman BC, Beddell CR, Lindon JC, Nicholson JK (1994) Pattern recognition classification of the site of nephrotoxicity based on metabolic data derived from proton nuclear magnetic resonance spectra of urine. Mol Pharmacol 46:199–211
Azuma Y, Maekawa M, Kuwabara Y, Nakajima T, Taniguchi K, Kanno T (1989) Determination of branched-chain amino acids and tyrosine in serum of patients with various hepatic diseases, and its clinical usefulness. Clin Chem 35:1399–1403
Beckwith-Hall BM, Nicholson JK, Nicholls AW, Foxall PJD, Lindon JC, Connor SC, Abdi M, Connelly J, Holmes E (1998) Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. Chem Res Toxicol 11:260–272
Bollard ME, Keun HC, Beckonert O, Ebbels TM, Antti H, Nicholls AW, Shockor JP, Cantor GH, Stevens G, Lindon JC, Holmes E, Nicholson JK (2005) Comparative metabonomics of differential hydrazine toxicity in the rat and mouse. Toxicol Appl Pharmacol 204:135–151
Cascales C, Martin-Sanz P, Pittner RA, Hopewell R, Brindley DN, Cascales M (1986) Effects of an antitumoural rhodium complex on thioacetamide-induced liver tumour in rats. Changes in the activities of ornithine decarboxylase, tyrosine aminotransferase and of enzymes involved in fatty acid and glycerolipid synthesis. Biochem Pharmacol 35:2655–2661
Clayton TA, Lindon JC, Everett JR, Charuel C, Hanton G, Le Net J-L, Provost J-P, Nicholson JK (2003) An hypothesis for a mechanism underlying hepatotoxin-induced hypercreatinuria. Arch Toxicol 77:208–217
Clayton TA, Lindon JC, Everett JR, Charuel C, Hanton G, Le Net J-L, Provost J-P, Nicholson JK (2004) Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status. Arch Toxicol 78:86–96
Coomes MW (1997) Amino acid metabolism. In: Devlin TM (ed) Textbook of biochemistry with clinical correlations, 4th edn. Wiley-Liss, New York
Decker K, Keppler D (1974) Galactosamine hepatitis: key role of the nucleotide deficiency period in the pathogenesis of cell injury and cell death. Rev Physiol Biochem Pharmacol 71:77–106
Ebadi M, Gessert CF, Al-Sayegh A (1982) Drug-pyridoxal phosphate interactions. Q Rev Drug Metab Interact 4:289–331
Erill S, Palacios G, Costa J, Laporte JR (1977) A comparison of the liver toxicity of isoniazid, cyanazide and their acetyl derivatives. In: Bundgaard, et al (eds) Drug design and adverse reactions. Munksgaard, Copenhagen, pp 89–98
Evans PJ (1981) The regulation of hepatic tyrosine aminotransferase. Biochim Biophys Acta 677:433–444
Farber E (1967) Ethionine fatty liver. Adv Lipid Res 5:119–183
Fontana L, Moreira E, Torres MI, Fernandez MI, Rios A, Sanchez de Medina F, Gil A (1996) Serum amino acid changes in rats with thioacetamide-induced liver cirrhosis. Toxicology 106:197–206
Fujikake Y (1981) A new rapid and simplified assay of major free amino acids in plasma and its clinical application (II). Determination of plasma free amino acids in various diseases of the liver and its application to differential diagnosis. Acta Sch Med Univ Gifu 29:822–837
Groenewald JV, Terblanche SE, Oelofsen W (1984) Tyrosine aminotransferase: characteristics and properties. Int J Biochem 16:1–18
Gross-Mesilaty S, Hargrove JL, Ciechanover A (1997) Degradation of tyrosine aminotransferase (TAT) via the ubiquitin-proteasome pathway. FEBS Lett 405:175–180
Hamm HH, Seubert W (1977) On the mechanism of inactivation and ATP-dependent reactivation of rat liver tyrosine aminotransferase. Z Naturforsch 32:777–780
Hershko A (2005) The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ 12:1191–1197
Hershko A, Tomkins GM (1971) Studies on the degradation of tyrosine aminotransferase in hepatoma cells in culture. J Biol Chem 246:710–714
Holmes E, Nicholls AW, Lindon JC, Connor SC, Connelly JC, Haselden JN, Damment SJ, Spraul M, Neidig P, Nicholson JK (2000) Chemometric models for toxicity classification based on NMR spectra of biofluids. Chem Res Tox 13:471–478
Hunter AL, Holscher MA, Neal RA (1977) Thioacetamide-induced hepatic necrosis. Involvement of the mixed-function oxidase enzyme system. J Pharmacol Exp Ther 200:439–448
Ito S (2003) IFPCS presidential lecture. A chemist’s view of melanogenesis. Pigment Cell Res 16:230–236
Joyeux H, Matias J, Saint-Aubert B, Astre C, Gouttebel MC, Vedrenne JB, Deneux L (1994–1995) Serum marker of the functional hepatic mass after extensive hepatectomy. The branched/aromatic amino acid ratio. Experimental and clinical studies. Chirurgie 120:283–288
Kawamura-Yasui N, Kaito M, Nakagawa N, Fujita N, Ikoma J, Gabazza EC, Watanabe S, Adachi Y (1999) Evaluating response to nutritional therapy using the branched-chain amino acid/tyrosine ratio in patients with chronic liver disease. J Clin Lab Anal 13:31–34
Kroger F, Gratz R (1979) Influence of DL-ethionine on the induction of tyrosine aminotransferase in the rat liver. Int J Biochem 10:1025–1031
Kroger H, Gratz R (1984) Induction of tyrosine aminotransferase under the influence of D-galactosamine. Int J Biochem 16:703–705
Lindon JC, Keun HC, Ebbels TM, Pearce JM, Holmes E, Nicholson JK (2005) The Consortium for Metabonomic Toxicology (COMET): aims, activities and achievements. Pharmacogenomics 6:691–699
Litwack G, Schmidt TJ (1997) Biochemistry of hormones I: polypeptide hormones. In: Devlin TM (ed) Textbook of biochemistry with clinical correlations, 4th edn. Wiley-Liss, New York
Mortishire-Smith RJ, Skiles GL, Lawrence JW, Spence S, Nicholls AW, Johnson BA, Nicholson JK (2004) Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity. Chem Res Toxicol 17:165–173
Nemeth S (1978) The effect of stress or glucose feeding on hepatic tyrosine aminotransferase activity and liver and plasma tyrosine level of intact and adrenalectomized rats. Horm Metab Res 10:144–147
Newsholme EA, Leech AR (1988) Biochemistry for the medical sciences. Wiley, Chichester, etc
Nicholson JK, Foxall PJD, Spraul M, Farrant RD, Lindon JC (1995) 750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. Anal Chem 67:793–811
Nicholson JK, Gartland KP (1989) 1H NMR studies on protein binding of histidine, tyrosine and phenylalanine in blood plasma. NMR Biomed 2:77–82
Nicholson JK, Lindon JC, Holmes E (1999) Metabonomics: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29:1181–1189
Nicholson JK, Wilson ID (1989) High-resolution proton magnetic resonance spectroscopy of biological fluids. Prog Nucl Mag Res Spec 21:449–501
Ozturk M, Lemonnier F, Cresteil D, Scotto J, Lemonnier A (1984) Methionine metabolism and ultrastructural changes with D-galactosamine in isolated rat hepatocytes. Chem Biol Interact 51:63–76
Pugge HR, Torrecilla A, Pellanda RJ (1979) Induction of tyrosine aminotransferase in galactosamine hepatitis. Acta Gastroenterol Latinoam 9:159–163
Rees KR, Rowland GF, Varcoe JS (1966) The metabolism of tritiated thioacetamide in the rat. Int J Cancer 1:197–206
Russo PA, Mitchell GA, Tanguay RM (2001) Tyrosinemia: a review. Pediatr Dev Pathol 4:212–221
Sanins SM, Nicholson JK, Elcombe C, Timbrell JA (1990) Hepatotoxin-induced hypertaurinuria: a proton NMR study. Arch Toxicol 64:407–411
Schmid E, Schmid W, Jantzen M, Mayer D, Jastorff B, Schutz G (1987) Transcription activation of the tyrosine aminotransferase gene by glucocorticoids and cAMP in primary hepatocytes. Eur J Biochem 165:499–506
Sequeira S, So PW, Everett JR, Elcombe CR, Kelvin AS, Nicholson JK (1990) 1H-NMR spectroscopy of biofluids and the investigation of xenobiotic-induced changes in liver biochemistry. J Pharm Biomed 8:945–949
Shelly LL, Yeoh GC (1991) Effects of dexamethasone and cAMP on tyrosine aminotransferase expression in cultured fetal rat hepatocytes. Eur J Biochem 199:475–481
Shiman R, Gray DW (1998) Formation and fate of tyrosine. Intracellular partitioning of newly synthesized tyrosine in mammalian liver. J Biol Chem 273:34760–34769
Skakun NP, Shmanko VV (1986) Efficacy of antioxidants in isoniazid-induced damage of the liver. Farmakol Toksikol 49:86–89
Slivka YI (1989) Comparative characterisation of hepatotoxicity of isoniazid, rifampicine and pyrazinamide. Farmakol Toksikol 52:82–85
Thomas BH, Solomonraj G (1977) Drug interaction with isoniazid metabolism in rats. J Pharmacol Sci 66:1322–1326
Timbrell JA (1991) Principles of biochemical toxicology, 2nd edn. Taylor and Francis, London and Washington DC
Waner T, Nyska A (1991) The toxicological significance of decreased activities of blood alanine and aspartate aminotransferase. Vet Res Commun 15:73–78
Acknowledgments
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Clayton, T.A., Lindon, J.C., Everett, J.R. et al. Hepatotoxin-induced hypertyrosinemia and its toxicological significance. Arch Toxicol 81, 201–210 (2007). https://doi.org/10.1007/s00204-006-0136-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-006-0136-7