Abstract
Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Metabolism, Inborn Errors / drug therapy*
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Amino Acid Metabolism, Inborn Errors / genetics
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Amino Acid Metabolism, Inborn Errors / pathology
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Amino Acids / blood
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Animals
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Cyclohexanones / therapeutic use*
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Cyclohexanones / toxicity
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Disease Models, Animal
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Enzyme Inhibitors / therapeutic use*
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Enzyme Inhibitors / toxicity
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Female
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Heptanoates / metabolism
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Humans
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Hydrolases / deficiency
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Liver / drug effects
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Liver / ultrastructure
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Liver Diseases / drug therapy*
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Liver Diseases / genetics
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Liver Diseases / pathology
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Liver Neoplasms / chemically induced
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Male
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Mice
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Mice, Inbred C57BL
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Nitrobenzoates / therapeutic use*
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Nitrobenzoates / toxicity
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Pancreas / pathology
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RNA, Messenger / metabolism
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Tyrosine / blood*
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alpha-Fetoproteins / metabolism
Substances
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Amino Acids
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Cyclohexanones
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Enzyme Inhibitors
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Heptanoates
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Nitrobenzoates
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RNA, Messenger
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alpha-Fetoproteins
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Tyrosine
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succinylacetone
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Hydrolases
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fumarylacetoacetase
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nitisinone