Reference SummaryStevenson WS, Proc Natl Acad Sci U S A 2010 Sep 21;107(38):16625-30

Title

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice.

Authors

Stevenson WS; Hyland CD; Zhang JG; Morgan PO; Willson TA; Gill A; Hilton AA; Viney EM; Bahlo M; Masters SL; Hennebry S; Richardson SJ; Nicola NA; Metcalf D; Hilton DJ; Roberts AW; Alexander WS

Journal

Proc Natl Acad Sci U S A

Volume

107

Issue

38

Year

2010

Pages

16625-30

Abstract

With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5-hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase in most vertebrate species. A point mutation in the gene encoding mouse HIU hydrolase, Urah, that perturbed uric acid metabolism within the liver was discovered during a mutagenesis screen in mice. The predicted substitution of cysteine for tyrosine in a conserved helical region of the mutant-encoded HIU hydrolase resulted in undetectable protein expression. Mice homozygous for this mutation developed elevated platelet counts secondary to excess thrombopoietin production and hepatomegaly. The majority of homozygous mutant mice also developed hepatocellular carcinoma, and tumor development was accelerated by exposure to radiation. The development of hepatomegaly and liver tumors in mice lacking Urah suggests that uric acid metabolites may be toxic and that urate oxidase activity without HIU hydrolase function may affect liver growth and transformation. The absence of HIU hydrolase in humans predicts slowed metabolism of HIU after clinical administration of exogenous urate oxidase in conditions of uric acid-related pathology. The data suggest that prolonged urate oxidase therapy should be combined with careful assessment of toxicity associated with extrahepatic production of uric acid metabolites.

Links

J:164423 – MGI References
20823251 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6-Urahplt2 Leukocyte - Lymphocyte leukemia Lymphoid tissue

observed

C57BL/6 Leukocyte - Lymphocyte leukemia Lymphoid tissue

observed

C57BL/6-Urahplt2 Liver hepatocellular carcinoma Liver

54.05

C57BL/6-Urahplt2 Liver hepatocellular carcinoma
  • radiation - unspecified type
Liver

88.89

C57BL/6 Liver hepatocellular carcinoma Liver

0

C57BL/6 Liver hepatocellular carcinoma
  • radiation - unspecified type
Liver

11.11

C57BL/6-Urahplt2 Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed

C57BL/6 Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed