title: Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway.
abstract: Hereditary tyrosinemia 1 (HT1) is characterized by progressive liver damage, from infancy, and by a high risk for hepatocellular carcinoma. HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. Lethal albino deletion c14CoS mice and mice with target-disrupted Fah are models for HT1, but they die in the perinatal period, albeit with a different phenotype from that seen in HT1 in humans. We first asked whether homozygous null mutation of the 4-hydroxyphenylpyruvate dioxygenase gene Hpd could rescue the homozygous c14CoS mice (c14CoS/c14CoS or Fah-/-). The double mutant Fah-/- Hpd-/- mice appeared normal, at least until age 18 months, and there was no evidence of liver disease, findings that facilitated examination of the effect of Fah-/- on mature and unmodified hepatocytes in vivo. The hepatocytes of Fah-/- undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed when Fah-/- Hpd-/- mice were administered homogentisate intraperitoneally. These changes in liver pathology in Fah-/- Hpd-/- mice after the administration of homogentisate were associated with massive urinary excretion of succinylacetone. These results suggest that accumulation of fumarylacetoacetate, maleylacetoacetate, or succinylacetone seems to trigger the endogenous process of apoptosis in hepatocytes that lack fumarylacetoacetate hydrolase activity. This apoptosis may be related to the development of hepatocellular carcinomas seen in HT1 patients and pharmaceutically treated fumarylacetoacetate hydrolase-deficient mice.
authors.affiliation: Department of Pediatrics, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto 860, Japan. endo@kaiju.medic.kumamoto-u.ac.jp
authors.forename: F
authors.initials: F
authors.lastname: Endo
authors.forename: S
authors.initials: S
authors.lastname: Kubo
authors.forename: H
authors.initials: H
authors.lastname: Awata
authors.forename: K
authors.initials: K
authors.lastname: Kiwaki
authors.forename: H
authors.initials: H
authors.lastname: Katoh
authors.forename: Y
authors.initials: Y
authors.lastname: Kanegae
authors.forename: I
authors.initials: I
authors.lastname: Saito
authors.forename: J
authors.initials: J
authors.lastname: Miyazaki
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
authors.forename: S
authors.initials: S
authors.lastname: Hattori
authors.forename: I
authors.initials: I
authors.lastname: Matsuda
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000235:genetics*; D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D008111:Liver Function Tests; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D014443:Tyrosine / Q000097:blood / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D015111:4-Hydroxyphenylpyruvate Dioxygenase