Extensive changes in liver gene expression induced by Hereditary Tyrosinemia type I are not normalized by treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC)

Background: Hereditary Tyrosinemia type I, caused by deficiency of fumarylacetoacetate hydrolase (FAH), is characterized by liver and kidney damage. Administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) corrects the tyrosinemia phenotype, but does not prevent development...

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Bibliographic Details
Published in:	Journal of hepatology Vol. 39; no. 6; pp. 901 - 909
Main Authors:	Luijerink, Marjanka C, Jacobs, Saskia M.M, van Beurden, Ellen A.C.M, Koornneef, Leander P, Klomp, Leo W.J, Berger, Ruud, van den Berg, Inge E.T
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier B.V 01-12-2003 Elsevier
Subjects:	2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) Animals Biological and medical sciences Blotting, Northern Cyclohexanones - pharmacology Digestive system DNA, Complementary Enzyme Inhibitors - pharmacology Female Fumarylacetoacetate hydrolase Gene Expression - drug effects Gene Expression Profiling Hepatocellular carcinoma Liver - physiology Liver damage Liver gene profiling Male Medical sciences Mice Mice, Inbred C57BL Mice, Mutant Strains Nitrobenzoates - pharmacology Pharmacology. Drug treatments Phenotype Reproducibility of Results Suppression subtractive hybridization Tyrosinemias - drug therapy Tyrosinemias - genetics Tyrosinemias - physiopathology Suppression subtractive hybridization Hepatocellular carcinoma Liver damage Fumarylacetoacetate hydrolase Liver gene profiling 2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) Tyrosinemia Suppression Hepatic disease Hybridization Enzymopathy Result Messenger RNA Substractive synthesis Complication Mechanism of action Aminoacid disorder Enzyme Deficiency Rodentia Metabolic diseases Gene expression Hereditary Genetic disease Vertebrata Mammalia Mouse Animal Digestive diseases Hydrolases
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Summary:	Background: Hereditary Tyrosinemia type I, caused by deficiency of fumarylacetoacetate hydrolase (FAH), is characterized by liver and kidney damage. Administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) corrects the tyrosinemia phenotype, but does not prevent development of hepatocellular carcinoma. Aim: To gain insight into the pathophysiological changes associated with liver damage induced by tyrosinemia and the preventive action of NTBC on these changes. Methods: Differential gene expression patterns in livers of tyrosinemia-affected and healthy mice, and of tyrosinemia-affected and NTBC-treated Fah −/− mice were investigated by suppression subtractive hybridization. Results: Transcripts encoding proteins playing a role in protein turnover, growth and proliferation, RNA processing, and signal transduction were primarily induced in tyrosinemia-affected livers. Transcripts mainly contributing to the profile of suppressed genes encode proteins that are secreted by the liver, or are necessary for intermediate metabolism. NTBC treatment fails to normalize the tyrosinemia-induced alterations in expression of transcripts encoding proteins involved in protein turnover, signal transduction, and cell growth and proliferation. Conclusions: The failure of NTBC to normalize liver gene expression of Fah −/− mice may play a role in rendering the tyrosinemia-affected liver susceptible to development of hepatocellular carcinoma under NTBC treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0168-8278 1600-0641
DOI:	10.1016/S0168-8278(03)00433-1