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

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

Author(s): 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;
Details: Publication Year 2010-09-21,Volume 107,Issue #38,Page 16625-16630
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
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 inmost 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.
Publisher: NATL ACAD SCIENCES
Keywords: N-ethyl-N-nitrosourea mutagenesis uric acid 5-hydroxyisourate hydrolase hepatocellular carcinoma thrombopoietin
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944704/
Publisher's Version: https://doi.org/10.1073/pnas.1010390107
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-09-21 12:00:00

Last Modified: 2014-12-23 12:16:00