1. Non-targeted metabolomics by high resolution mass spectrometry in HPRT knockout mice.
- Author
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Tschirner SK, Bähre H, Kaever A, Schneider EH, Seifert R, and Kaever V
- Subjects
- Aminoimidazole Carboxamide analogs & derivatives, Aminoimidazole Carboxamide pharmacology, Animals, Biomarkers metabolism, Brain metabolism, Hypoxanthine Phosphoribosyltransferase metabolism, Imidazoles pharmacology, Mice, Knockout, Principal Component Analysis, Ribonucleotides pharmacology, Hypoxanthine Phosphoribosyltransferase deficiency, Mass Spectrometry methods, Metabolomics methods
- Abstract
Aims: Lesch-Nyhan disease (LND) is characterized by hyperuricemia as well as neurological and neuropsychiatric symptoms including repetitive self-injurious behavior. Symptoms are caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a result of a mutation on the X chromosome. To elucidate the pathophysiology of LND, we performed a metabolite screening for brain and serum extracts from HPRT knockout mice as an animal model for LND., Main Methods: Analyses were performed by high performance liquid chromatography (HPLC)-coupled quadrupole time-of-flight mass spectrometry (QTOF-MS)., Key Findings: In brain extracts, we found six metabolites with significantly different contents in wild-type and HPRT-deficient mice. Two compounds we could identify as 5-aminoimidazole-4-carboxamide ribotide (AICAR) and 1-methylimidazole-4-acetic acid (1-MI4AA). Whereas AICAR was accumulated in brains of HPRT knockout mice, 1-MI4AA was decreased in these mice., Significance: Both metabolites play a role in histidine metabolism and, as a consequence, histamine metabolism. AICAR, in addition, is part of the purine metabolism. Our findings may help to better understand the mechanisms leading to the behavioral phenotype of LND., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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