carcinogenic effects in a phenylketonuria mouse model致癌的苯丙酮尿症小鼠模型.pdfVIP

Carcinogenic Effects in a Phenylketonuria Mouse Model 1 1 2 3 Neil Sidell *, Lijuan Hao , Marzia Pasquali , J. David McDonald 1 Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, United States of America, 2 Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America, 3 Department of Biological Sciences, Wichita State University, Wichita, Kansas, United States of America Abstract 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 (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 tu