title: Non-targeted metabolomics by high resolution mass spectrometry in HPRT knockout mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Analyses were performed by high performance liquid chromatography (HPLC)-coupled quadrupole time-of-flight mass spectrometry (QTOF-MS).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: tschirner.sarah@mh-hannover.de.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tschirner
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; Research Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: baehre.heike@mh-hannover.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Bähre
authors.affiliation: Department of Bioinformatics, Institute of Microbiology and Genetics, Georg-August-University Göttingen, Goldschmidtstr. 1, D-37077 Göttingen, Germany. Electronic address: alex@gobics.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kaever
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: schneider.erich@mh-hannover.de.
authors.forename: Erich H
authors.initials: EH
authors.lastname: Schneider
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: seifert.roland@mh-hannover.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; Research Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: kaever.volkhard@mh-hannover.de.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D013058:Mass Spectrometry / Q000379:methods*; D055432:Metabolomics / Q000379:methods*; D018345:Mice, Knockout; D025341:Principal Component Analysis; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D007093:Imidazoles; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D007041:Hypoxanthine Phosphoribosyltransferase; C031143:AICA ribonucleotide; C018100:1-methylimidazole
keywords: 1-Methylimidazole-4-acetic acid; AICAR; HPRT knockout mice; Lesch-Nyhan disease; Mass spectrometry; Non-targeted metabolomics