Complete Rescue of Lethal Albino c Mice by Null Mutation of 4-Hydroxyphenylpyruvate Dioxygenase and Induction of Apoptosis of Hepatocytes in These Mice by in VivoRetrieval 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 c 14CoS 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 c 14CoS mice (c 14CoS /c 14CoS 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.

The Caenorhabditis elegans K10C2.4 Gene Encodes a Member of the Fumarylacetoacetate Hydrolase Family

“…These findings are particularly important as they demonstrate the functional identity of the predicted homologs and order the genes in the degradation pathway at a genetic level. These results are also consistent with findings from fungal and mouse models where mutations in upstream genes are able to rescue the lethality associated with FAH mutations (14,44,49,50).…”

“…4). Both mice and fungi with FAH mutations are rescued by mutations in the 4-hydroxyphenylpyruvate dioxygenase and homogentisate dioxygenase genes (14,44,49,50). We find that the phenotype is critically dependent on an intact tyrosine degradation pathway, because combining K10C2.4 RNAi with RNAi directed against F42D1.2, T21C12.2, or W06D4.1 is able to completely rescue treated worms from the effects of K10C2.4 RNAi (Fig.…”

“…Organ damage is likely due to the accumulation of MAA, FAA, and their conversion to succinylacetoacetate (SAA) and succinylacetone (SA) (12). These compounds are highly reactive electrophiles, which can damage proteins and DNA leading to the activation of several stress response pathways as well as apoptotic pathways (13)(14)(15)(16)(17)(18)(19)(20).…”

Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death

“…However, acute administration of HGA, a tyrosine metabolite downstream of the HPD enzyme, can evoke a massive apoptotic response in hepatocytes of these animals. 12,16 FAA itself can also induce apoptosis of cultured cells. 11 To confirm these findings, HGA was injected i.p.…”

Mechanistic Inferences from the Crystal Structure of Fumarylacetoacetate Hydrolase with a Bound Phosphorus-based Inhibitor

“…The lethal nature of HT1 is most likely due to the accumulation of the toxic intermediate fumarylacetoacetate in the absence of FAH activity (4 -6). This reactive metabolite may cause direct DNA (7) and tissue damage, depletion of cellular glutathione levels (8,9), and induction of apoptosis (10). HT1 is currently treated by combined liver/kidney transplantation (11) and pharmacologic inhibition of hydroxyphenylpyruvate dioxygenase (12), which catalyzes an earlier step in Phe/Tyr catabolism.…”