Hepatotoxin-induced hypertyrosinemia and its toxicological significance

被引:16
作者
Clayton, T. Andrew
Lindon, John C.
Everett, Jeremy R.
Charuel, Claude
Hanton, Gilles
Le Net, Jean-Loic
Provost, Jean-Pierre
Nicholson, Jeremy K.
机构
[1] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Biomol Med, London SW7 2AZ, England
[2] Pfizer Global R&D, Sandwich CT13 9NJ, Kent, England
[3] Pfizer Global R&D, Ctr Rech, F-37401 Ambroise, France
关键词
ethionine; galactosamine; isoniazid; thioacetamide; liver; hypertyrosinemia; tyrosine aminotransferase; rat;
D O I
10.1007/s00204-006-0136-7
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
A H-1 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).
引用
收藏
页码:201 / 210
页数:10
相关论文
共 51 条
[1]  
ANTHONY ML, 1994, MOL PHARMACOL, V46, P199
[2]  
AZUMA Y, 1989, CLIN CHEM, V35, P1399
[3]   Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins [J].
Beckwith-Hall, BM ;
Nicholson, JK ;
Nicholls, AW ;
Foxall, PJD ;
Lindon, JC ;
Connor, SC ;
Abdi, M ;
Connelly, J ;
Holmes, E .
CHEMICAL RESEARCH IN TOXICOLOGY, 1998, 11 (04) :260-272
[4]   Comparative metabonomics of differential hydrazine toxicity in the rat and mouse [J].
Bollard, ME ;
Keun, HC ;
Beckonert, O ;
Ebbels, TMD ;
Antti, H ;
Nicholls, AW ;
Shockcor, JP ;
Cantor, GH ;
Stevens, G ;
Lindon, JC ;
Holmes, E ;
Nicholson, JK .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2005, 204 (02) :135-151
[5]   EFFECTS OF AN ANTITUMORAL RHODIUM COMPLEX ON THIOACETAMIDE-INDUCED LIVER-TUMOR IN RATS - CHANGES IN THE ACTIVITIES OF ORNITHINE DECARBOXYLASE, TYROSINE AMINOTRANSFERASE AND OF ENZYMES INVOLVED IN FATTY-ACID AND GLYCEROLIPID SYNTHESIS [J].
CASCALES, C ;
MARTINSANZ, P ;
PITTNER, RA ;
HOPEWELL, R ;
BRINDLEY, DN ;
CASCALES, M .
BIOCHEMICAL PHARMACOLOGY, 1986, 35 (16) :2655-2661
[6]   Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status [J].
Clayton, TA ;
Lindon, JC ;
Everett, JR ;
Charuel, C ;
Hanton, G ;
Le Net, JL ;
Provost, JP ;
Nicholson, JK .
ARCHIVES OF TOXICOLOGY, 2004, 78 (02) :86-96
[7]   An hypothesis for a mechanism underlying hepatotoxin-induced hypercreatinuria [J].
Clayton, TA ;
Lindon, JC ;
Everett, JR ;
Charuel, C ;
Hanton, G ;
Le Net, JL ;
Provost, JP ;
Nicholson, JK .
ARCHIVES OF TOXICOLOGY, 2003, 77 (04) :208-217
[8]  
COOMES MW, 1997, TXB BIOCH CLIN CORRE
[9]   GALACTOSAMINE HEPATITIS - KEY ROLE OF THE NUCLEOTIDE DEFICIENCY PERIOD IN THE PATHOGENESIS OF CELL INJURY AND CELL-DEATH [J].
DECKER, K ;
KEPPLER, D .
REVIEWS OF PHYSIOLOGY BIOCHEMISTRY AND PHARMACOLOGY, 1974, 71 :77-106
[10]  
Ebadi M, 1982, Q Rev Drug Metab Drug Interact, V4, P289