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Carcinogenic Effects in a Phenylketonuria Mouse Model

Phenylketonuria (PKU) is a metabolic disorder caused by impaired phenylalanine hydroxylase (PAH). This condition results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites, among which is phenylacetic acid/phenylacetate (PA). In recent years, PA and its analogs were f...

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Detalles Bibliográficos
Autores principales: Sidell, Neil, Hao, Lijuan, Pasquali, Marzia, McDonald, J. David
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2625399/
https://www.ncbi.nlm.nih.gov/pubmed/19172175
http://dx.doi.org/10.1371/journal.pone.0004292
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author Sidell, Neil
Hao, Lijuan
Pasquali, Marzia
McDonald, J. David
author_facet Sidell, Neil
Hao, Lijuan
Pasquali, Marzia
McDonald, J. David
author_sort Sidell, Neil
collection PubMed
description Phenylketonuria (PKU) is a metabolic disorder caused by impaired phenylalanine hydroxylase (PAH). This condition results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites, among which is phenylacetic acid/phenylacetate (PA). In recent years, PA and its analogs were found to have anticancer activity against a variety of malignancies suggesting the possibility that PKU may offer protection against cancer through chronically elevated levels of PA. We tested this hypothesis in a genetic mouse model of PKU (PAH(enu2)) which has a biochemical profile that closely resembles that of human PKU. Plasma levels of phenylalanine in homozygous (HMZ) PAH(enu2) mice were >12-fold those of heterozygous (HTZ) littermates while tyrosine levels were reduced. Phenylketones, including PA, were also markedly elevated to the range seen in the human disease. Mice were subjected to 7,12 dimethylbenz[a]anthracene (DMBA) carcinogenesis, a model which is sensitive to the anticancer effects of the PA derivative 4-chlorophenylacetate (4-CPA). Tumor induction by DMBA was not significantly different between the HTZ and HMZ mice, either in total tumor development or in the type of cancers that arose. HMZ mice were then treated with 4-CPA as positive controls for the anticancer effects of PA and to evaluate its possible effects on phenylalanine metabolism in PKU mice. 4-CPA had no effect on the plasma concentrations of phenylalanine, phenylketones, or tyrosine. Surprisingly, the HMZ mice treated with 4-CPA developed an unexplained neuromuscular syndrome which precluded its use in these animals as an anticancer agent. Together, these studies support the use of PAH(enu2) mice as a model for studying human PKU. Chronically elevated levels of PA in the PAH(enu2) mice were not protective against cancer.
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spelling pubmed-26253992009-01-27 Carcinogenic Effects in a Phenylketonuria Mouse Model Sidell, Neil Hao, Lijuan Pasquali, Marzia McDonald, J. David PLoS One Research Article Phenylketonuria (PKU) is a metabolic disorder caused by impaired phenylalanine hydroxylase (PAH). This condition results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites, among which is phenylacetic acid/phenylacetate (PA). In recent years, PA and its analogs were found to have anticancer activity against a variety of malignancies suggesting the possibility that PKU may offer protection against cancer through chronically elevated levels of PA. We tested this hypothesis in a genetic mouse model of PKU (PAH(enu2)) which has a biochemical profile that closely resembles that of human PKU. Plasma levels of phenylalanine in homozygous (HMZ) PAH(enu2) mice were >12-fold those of heterozygous (HTZ) littermates while tyrosine levels were reduced. Phenylketones, including PA, were also markedly elevated to the range seen in the human disease. Mice were subjected to 7,12 dimethylbenz[a]anthracene (DMBA) carcinogenesis, a model which is sensitive to the anticancer effects of the PA derivative 4-chlorophenylacetate (4-CPA). Tumor induction by DMBA was not significantly different between the HTZ and HMZ mice, either in total tumor development or in the type of cancers that arose. HMZ mice were then treated with 4-CPA as positive controls for the anticancer effects of PA and to evaluate its possible effects on phenylalanine metabolism in PKU mice. 4-CPA had no effect on the plasma concentrations of phenylalanine, phenylketones, or tyrosine. Surprisingly, the HMZ mice treated with 4-CPA developed an unexplained neuromuscular syndrome which precluded its use in these animals as an anticancer agent. Together, these studies support the use of PAH(enu2) mice as a model for studying human PKU. Chronically elevated levels of PA in the PAH(enu2) mice were not protective against cancer. Public Library of Science 2009-01-27 /pmc/articles/PMC2625399/ /pubmed/19172175 http://dx.doi.org/10.1371/journal.pone.0004292 Text en Sidell et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sidell, Neil
Hao, Lijuan
Pasquali, Marzia
McDonald, J. David
Carcinogenic Effects in a Phenylketonuria Mouse Model
title Carcinogenic Effects in a Phenylketonuria Mouse Model
title_full Carcinogenic Effects in a Phenylketonuria Mouse Model
title_fullStr Carcinogenic Effects in a Phenylketonuria Mouse Model
title_full_unstemmed Carcinogenic Effects in a Phenylketonuria Mouse Model
title_short Carcinogenic Effects in a Phenylketonuria Mouse Model
title_sort carcinogenic effects in a phenylketonuria mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2625399/
https://www.ncbi.nlm.nih.gov/pubmed/19172175
http://dx.doi.org/10.1371/journal.pone.0004292
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