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J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Aug 15;1060:347-354. doi: 10.1016/j.jchromb.2017.06.030. Epub 2017 Jun 19.

Comprehensive analysis of the tryptophan metabolome in urine of patients with acute intermittent porphyria.

Author information

1
Integrative Pharmacology and Systems Neuroscience Group, IMIM, Hospital del Mar, Doctor Aiguader 88, Barcelona, Spain; Programa De Recerca En Epidemiologia I Salut Pública, ISGlobal, Campus Mar, Doctor Aiguader 88, Barcelona, Spain; Universitat Pompeu Fabra (CEXS-UPF), Doctor Aiguader 88, Barcelona, Spain. Electronic address: agomezgo20@gmail.com.
2
Universitat Pompeu Fabra (CEXS-UPF), Doctor Aiguader 88, Barcelona, Spain; Cerba Internacional, Pl. Ramon Llull, 7, 08203 Sabadell, Spain. Electronic address: josep.marcos@upf.edu.
3
Porphyria Unit, Dermatology Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Villarrroel 170, Barcelona, Spain. Electronic address: PAGUILE@clinic.ub.es.
4
Biochemistry and Molecular Genetics Unit, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Villarroel 170, Barcelona, Spain. Electronic address: JTO@clinic.cat.
5
Integrative Pharmacology and Systems Neuroscience Group, IMIM, Hospital del Mar, Doctor Aiguader 88, Barcelona, Spain. Electronic address: opozo@imim.es.

Abstract

BACKGROUND:

Acute intermittent porphyria (AIP) is a rare metabolic disorder due to a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. This low enzymatic activity may predispose to the appearance of acute neurological attacks. Seminal studies suggested that AIP was associated with changes in tryptophan homeostasis with inconclusive results. Therefore, the aim of this study was to analyze the urinary metabolome of AIP patients focusing on tryptophan metabolism using state-of-the-art technology.

METHODS:

This was a case-control study including a group of 25 AIP patients with active biochemical disease and increased excretion of heme-precursors and 25 healthy controls. Tryptophan and related compounds and metabolites including: large neutral amino acids (LNAAs), serotonin, kynurenine, kynurenic acid and anthranilic acid were quantified in urine by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Twenty-nine biological markers (including metabolic ratios and absolute concentrations) were compared between patients and controls.

RESULTS:

Significant differences were found in the tryptophan-kynurenine metabolic pathway. Compared to controls, AIP patients showed: (a) increased urinary excretion of kynurenine and anthranilic acid (P<0.005); (b): elevation of the kynurenine/tryptophan ratio (P<0.001) and (c): decrease of the kynurenic acid/kynurenine ratio (P=0.001). In contrast, no differences were found in the serotonin metabolic pathway independently of the markers and ratios used.

CONCLUSIONS:

The results of the study demonstrate that there is an imbalance in the kynurenine metabolic pathway in AIP patients, with an increase of the kynurenine/tryptophan ratio in urine and a reduction of the kynurenic acid/kynurenine ratio. The modified ratios suggest induction of indoleamine 2,3-deoxygenase and decreased activity of kynurenine aminotransferase in the liver. The results confirm that LC-MS/MS is useful for the characterization of the urinary metabolome of hepatic porphyrias.

KEYWORDS:

Acute intermittent porphyria; Kynurenine; Mass spectrometry; Metabolomics; Serotonin; Tryptophan

PMID:
28666226
DOI:
10.1016/j.jchromb.2017.06.030
[Indexed for MEDLINE]

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