fumarylacetoacetate and Disease-Models--Animal

Mice with humanized chimeric liver are promising in vivo tools to evaluate the efficacy of novel compounds or vaccine induced antibodies directed against pathogens that infect the human liver. In addition they can be used to study the human-type metabolism of medicinal compounds and hepatotoxicity.

Topics: Acetoacetates; Animals; Cell Transplantation; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Hepatocytes; Humans; Hydrolases; Liver; Mice; Mice, Knockout; Mice, SCID; Transplantation Chimera; Urokinase-Type Plasminogen Activator

Hereditary tyrosinemia type I and alkaptonuria are disorders of tyrosine catabolism caused by deficiency of fumarylacetoacetate hydrolase (FAH) and homogentisic acid dioxygenase (HGD), respectively. Tyrosinemia is a severe childhood disease that affects the liver and kidneys, but alkaptonuria is a more benign adult disorder in comparison. Because HGD is upstream of FAH in the tyrosine pathway, mice doubly mutant in both enzymes were found to be protected from the liver and renal damage of tyrosinemia as hypothesized. Mice mutant at the tyrosinemic locus but heterozygous for alkaptonuria spontaneously developed clonal nodules of functionally normal hepatocytes that were able to rescue the livers of some mice with this genotype. This phenotypic rescue was a result of an inactivating mutation of the wild-type homogentisic acid dioxygenase gene, thus presenting an example of an in vivo suppressor mutation in a mammalian model.

Topics: Acetoacetates; Alanine Transaminase; Animals; Cloning, Molecular; Crosses, Genetic; Disease Models, Animal; Ethylnitrosourea; Gene Conversion; Gene Deletion; Genotype; Heterozygote; Liver; Loss of Heterozygosity; Mice; Mice, Knockout; Models, Genetic; Mutagenesis; Precancerous Conditions; Reverse Transcriptase Polymerase Chain Reaction; Suppression, Genetic; Tyrosine; Tyrosinemias

Tyrosinemia type 1, caused by mutations in the fumarylacetoacetate hydrolase gene (Fah), is characterized by severe liver injury. We earlier developed a tyrosinemic mouse model with two genetic defects, Fah and 4-hydroxyphenylpyruvate dioxygenase (Hpd) deficiencies. Apoptosis of hepatocytes was induced and an acute onset of liver failure occurred after administration of homogentisic acid (HGA), the intermediate metabolite between the enzymes HPD and FAH. Cytochrome c was released from mitochondria prior to liver failure in the Fah-/- Hpd-/- double-mutant mice after the administration of HGA. In a cell-free system, the addition of fumarylacetoacetate induced the release of cytochrome c from the mitochondria. We also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double-mutant mice. Therefore, fumarylacetoacetate apparently induces the release of cytochrome c, which in turn triggers activation of the caspase cascade in hepatocytes of subjects with hereditary tyrosinemia type 1.

Topics: Acetoacetates; Amino Acid Metabolism, Inborn Errors; Animals; Apoptosis; Cell-Free System; Cysteine Proteinase Inhibitors; Cytochrome c Group; Disease Models, Animal; Liver; Mice; Mice, Knockout; Mitochondria, Liver; Tyrosine