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dc.contributor.authorSidell, Neil
dc.contributor.authorHao, Lijuan
dc.contributor.authorPasquali, Marzia
dc.contributor.authorMcDonald, J. David
dc.date.accessioned2013-04-17T18:46:06Z
dc.date.available2013-04-17T18:46:06Z
dc.date.issued2009-01-27
dc.identifier.citationSidell, Neil; Hao, Lijuan; Pasquali, Marzia; McDonald, J. David. 2009. Carcinogenic effects in a phenylketonuria mouse model. PLoS ONE v.4 no.1 e4292en_US
dc.identifier.othere4292
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0004292
dc.identifier.urihttp://hdl.handle.net/10057/5628
dc.descriptionThis 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 credited.en_US
dc.description.abstractPhenylketonuria (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 (PAHenu2) which has a biochemical profile that closely resembles that of human PKU. Plasma levels of phenylalanine in homozygous (HMZ) PAHenu2 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 PAHenu2 mice as a model for studying human PKU. Chronically elevated levels of PA in the PAHenu2 mice were not protective against cancer.en_US
dc.language.isoen_USen_US
dc.publisherPubMeden_US
dc.relation.ispartofseriesPLoS ONE;v.4 no.1 e4292
dc.titleCarcinogenic effects in a phenylketonuria mouse modelen_US
dc.typeArticleen_US


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