title: 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).
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Metabolic Diseases, Laboratory for Metabolic and Endocrine Diseases, Room KC02.069.1, University Medical Center, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
authors.forename: Marjanka C
authors.initials: MC
authors.lastname: Luijerink
authors.forename: Saskia M M
authors.initials: SM
authors.lastname: Jacobs
authors.forename: Ellen A C M
authors.initials: EA
authors.lastname: van Beurden
authors.forename: Leander P
authors.initials: LP
authors.lastname: Koornneef
authors.forename: Leo W J
authors.initials: LW
authors.lastname: Klomp
authors.forename: Ruud
authors.initials: R
authors.lastname: Berger
authors.forename: Inge E T
authors.initials: IE
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D003512:Cyclohexanones / Q000494:pharmacology*; D018076:DNA, Complementary; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008099:Liver / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009579:Nitrobenzoates / Q000494:pharmacology*; D010641:Phenotype; D015203:Reproducibility of Results; D020176:Tyrosinemias / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology
chemical_list: D003512:Cyclohexanones; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; C077073:nitisinone