The major limitations in studying the biochemical variables of phenylketonuria in human patients are as follows: (1) Multiple mutations in the phenylalanine hydroxylase locus resulting in different extent of residual enzymatic activity; (2) Limitations in the compliance to dietary management; (3) Limited number of specimens from various physiological fluids and tissues that could be obtained for studies The major advantage in using the murine model of phenylketonuria is that these restrictions do not exist and each of the variables could be evaluated separately In the present study, mice with a mutation in the phenylalanine hydroxylase enzyme (a missense mutation in Exon 7 at codon 263) were studied. A mutation at the same locus occurs also in human patients and in both mice and humans the mutation leads to undetectable activity of phenylalanine hydroxylase We evaluated the plasma amino acids and urinary metabolites of the alternate pathway of phenylalanine in PKU Mice (PahEnu2) and control mice from the same strain (BTBR) on unrestricted and restricted phenylalanine intakes. It was shown that plasma phenylalanine levels reflected the dietary phenylalanine intake. Plasma tyrosine levels were significantly higher in PKU mice on a restricted phenylalanine intake when compared to PKU mice on an unrestricted phenylalanine intake. Significant decreases in plasma glycine levels in PKU mice on an unrestricted phenylalanine intake were observed as compared to PKU mice on a restricted phenylalanine intake and to control mice It was also shown that the alternate pathway metabolites of phenylalanine (phenylpyruvic, phenylacetic, ortho-hydroxyphenylacetic, phenyllactic, and mandelic acids, and phenylacetylglycine) were excreted in parallel to the plasma phenylalanine levels. An interesting observation was that the phenylacetylglycine was shown to be the best predictor of the plasma phenylalanine levels in mice. This glycine conjugate has not been previously described in human patients In another group of mice and controls the phenylalanine intake was gradually increased to approximately four-fold that of the normal diet and than gradually decreased to a markedly restricted phenylalanine intake. A reverse ratio was documented between plasma phenylalanine and glycine levels in the PKU mice. Also, in PKU mice on restricted and unrestricted phenylalanine intakes, phenylacetylglycine was shown to be the best predictor of the plasma phenylalanine levels An interesting observation was the loss of the fur color in untreated PKU mice (which reversed with treatment) with intermediate changes in partially treated PKU mice and no changes in treated PKU mice Histological studies with light microscopy did not reveal any significant changes in control or PKU mice on unrestricted and restricted phenylalanine intakes Considering the analogy between the murine and human phenylketonuria this model could be further used to study the biochemical and nutritional problems in this disease / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_24559 |
| Date | January 1997 |
| Contributors | Lewis, Vyoone Therese (Author), Shapira, Emmanuel (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Access requires a license to the Dissertations and Theses (ProQuest) database., Copyright is in accordance with U.S. Copyright law |
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