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Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice.(MEDICAL SCIENCES)(Author abstract)(Report)

With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5ureidoimidazoline decarboxylase in most vertebrate species. A point mutation in the gene encoding mouse H... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States Sept 21, 2010, Vol.107(38), p.16625(6)
Main Author: Stevenson, William S.
Other Authors: Hyland, Craig D. , Zhang, Jian - Guo , Morgan, Phillip O. , Willson, Tracy A. , Gill, Anthony , Hilton, Adrienne A. , Viney, Elizabeth M. , Bahlo, Melanie , Masters, Seth L. , Hennebry, Sarah , Richardson, Samantha J. , Nicola, Nicos A. , Metcalf, Donald , Hilton, Douglas J. , Roberts, Andrew W. , Alexander, Warren S.
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Cengage Learning, Inc.
ID: ISSN: 0027-8424
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recordid: gale_ofa238553498
title: Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice.(MEDICAL SCIENCES)(Author abstract)(Report)
format: Article
creator:
  • Stevenson, William S.
  • Hyland, Craig D.
  • Zhang, Jian - Guo
  • Morgan, Phillip O.
  • Willson, Tracy A.
  • Gill, Anthony
  • Hilton, Adrienne A.
  • Viney, Elizabeth M.
  • Bahlo, Melanie
  • Masters, Seth L.
  • Hennebry, Sarah
  • Richardson, Samantha J.
  • Nicola, Nicos A.
  • Metcalf, Donald
  • Hilton, Douglas J.
  • Roberts, Andrew W.
  • Alexander, Warren S.
subjects:
  • Hepatocellular Carcinoma -- Causes Of
  • Uric Acid -- Health Aspects
  • Hepatomegaly -- Causes Of
  • Hydrolases -- Health Aspects
ispartof: Proceedings of the National Academy of Sciences of the United States, Sept 21, 2010, Vol.107(38), p.16625(6)
description: With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5ureidoimidazoline 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 mutantencoded 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. N-ethyl-N-nitrosourea mutagenesis | uric acid | 5-hydroxyisourate hydrolase | hepatocellular carcinoma | thrombopoietin doi/ 10.1073/pnas.1010390107
language: English
source: Cengage Learning, Inc.
identifier: ISSN: 0027-8424
fulltext: fulltext
issn:
  • 0027-8424
  • 00278424
url: Link


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titleDeficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice.(MEDICAL SCIENCES)(Author abstract)(Report)
creatorStevenson, William S. ; Hyland, Craig D. ; Zhang, Jian - Guo ; Morgan, Phillip O. ; Willson, Tracy A. ; Gill, Anthony ; Hilton, Adrienne A. ; Viney, Elizabeth M. ; Bahlo, Melanie ; Masters, Seth L. ; Hennebry, Sarah ; Richardson, Samantha J. ; Nicola, Nicos A. ; Metcalf, Donald ; Hilton, Douglas J. ; Roberts, Andrew W. ; Alexander, Warren S.
ispartofProceedings of the National Academy of Sciences of the United States, Sept 21, 2010, Vol.107(38), p.16625(6)
identifierISSN: 0027-8424
subjectHepatocellular Carcinoma -- Causes Of ; Uric Acid -- Health Aspects ; Hepatomegaly -- Causes Of ; Hydrolases -- Health Aspects
descriptionWith the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5ureidoimidazoline 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 mutantencoded 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. N-ethyl-N-nitrosourea mutagenesis | uric acid | 5-hydroxyisourate hydrolase | hepatocellular carcinoma | thrombopoietin doi/ 10.1073/pnas.1010390107
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titleDeficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice.(MEDICAL SCIENCES)(Author abstract)(Report)
descriptionWith the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5ureidoimidazoline 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 mutantencoded 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. N-ethyl-N-nitrosourea mutagenesis | uric acid | 5-hydroxyisourate hydrolase | hepatocellular carcinoma | thrombopoietin doi/ 10.1073/pnas.1010390107
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abstractWith the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5ureidoimidazoline 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 mutantencoded 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. N-ethyl-N-nitrosourea mutagenesis | uric acid | 5-hydroxyisourate hydrolase | hepatocellular carcinoma | thrombopoietin doi/ 10.1073/pnas.1010390107
pubNational Academy of Sciences
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