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Biomarkers of serotonin metabolism: Diagnostic, monitoring and pharmacogenetic interest

Titel Englisch Biomarkers of serotonin metabolism: Diagnostic, monitoring and pharmacogenetic interest
Gesuchsteller/in Buclin Thierry
Nummer 146166
Förderungsinstrument Projektförderung (Abt. I-III)
Forschungseinrichtung Division de Pharmacologie et Toxicologie Cliniques CHUV, Hôpital de Beaumont
Hochschule Universität Lausanne - LA
Hauptdisziplin Klinische Pharmakologie
Beginn/Ende 01.04.2013 - 30.09.2017
Bewilligter Betrag 400'920.00
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Alle Disziplinen (4)

Disziplin
Klinische Pharmakologie
Klinische Krebsforschung
Klinische Endokrinologie
Innere Medizin

Keywords (9)

Diagnostic tests; Cancer biomarkers; Serotonin; Pharmacogenetics; Cytochromes CYP2D6; Cytochromes CYP1A2; Carcinoid tumor; Melatonin; Pheotyping test

Lay Summary (Französisch)

Lead
Les métabolites de la sérotonine pourraient fournir de nouveaux marqueurs d’importance diagnostique et thérapeutique pour la caractérisation de traits pharmacogénétiques, les investigations psychopharmacologiques ainsi que le diagnostic et le suivi des tumeurs carcinoïdes.
Lay summary

La sérotonine est un neurotransmetteur impliqué dans de nombreux processus physiologiques. Elle affecte le sommeil, l’humeur, le rythme circadien, l’appétit, les régulations métaboliques et la réponse à maints traitements médicamenteux. Son  métabolisme, relié à celui de la mélatonine, implique des enzymes clés (comme les cytochromes P450) connus pour présenter une importante variabilité entre individus, et parfois chez un même individu. A ce jour, aucun substrat endogène n’est validé pour tester leur fonction. La détermination in vivo de l’activité de ces enzymes nécessite l’administration de substances exogènes en conditions contrôlées. Une détermination à partir de ratios de métabolites endogènes sur un échantillon de sang ou d’urine pourrait fournir des outils diagnostiques pour les maladies impliquant la sérotonine, les processus mentaux et les variations pharmacogénétiques. De plus, la sérotonine est produite en excès par les tumeurs carcinoïdes, une forme rare de cancer difficile à diagnostiquer avec les marqueurs actuellement disponibles, que les métabolites intermédiaires de la sérotonine pourraient remplacer.

Concrètement, ce projet vise (1) à mesurer une série de métabolites intermédiaires de la sérotonine dans le sang et l’urine, (2) à définir leurs valeurs normales chez l’homme, (3) à identifier ceux qui pourraient améliorer le dépistage des tumeurs carcinoïdes, (4) à déterminer l’influence des médicaments affectant la transmission ou le métabolisme de la sérotonine, (5) à observer leurs modifications dans des conditions pathologiques telles que le syndrome sérotoninergique, et (6) à corréler leur association avec des polymorphismes génétiques affectant certains enzymes.

Direktlink auf Lay Summary Letzte Aktualisierung: 18.04.2013

Lay Summary (Englisch)

Lead
Serotonin metabolites may provide novel markers of potential diagnostic and therapeutic relevance for pharmacogenetic phenotyping, psychopharmacological investigations and carcinoid tumor diagnosis and follow up.
Lay summary

Serotonin is a neurotransmiter involved in many physiological processes. It affects sleep, mood, circadian rhythm, appetite, metabolic regulations, as well as the response to many drugs and medicines. Its metabolism, closely related to melatonin, involves key enzymes (e.g. cytochrome P450) exhibiting inter and intra-individual functional variability.

To date, no endogenous substrate is validated as test probe. The in vivo determination of enzymatic activity needs time consuming procedures with probe substance administration under controlled conditions. Determining enzyme activity from endogenous serotonin metabolites and ratio calculations on a single blood/urine sample could offer new diagnostic tools regarding serotonin-related diseases, neurocognitive processes and pharmacogenetic traits. Moreover, serotonin is produced by carcinoid tumors, a rare form of cancer difficult to diagnose with the currently available, suboptimal markers. Screening blood and urine serotonin metabolites may thus also allow identifying new biomarkers of these specific tumors.

Concretely, this project aims (1) to measure an array of serotonin metabolites in humans, (2) to define normal ranges for these metabolites and their ratios in healthy volunteers, (3) to identify potential candidate metabolites that would better perform as biomarkers for carcinoid tumor diagnosis, (4) to assess the influence of drugs affecting serotoninergic transmission or biotransformation on these metabolites, (5) to determine whether their concentrations are modulated during pathological conditions such as serotoninergic syndrome, (6) to correlate the activity of genetically polymorphic enzymes with the measurement of endogenous metabolites.

Direktlink auf Lay Summary Letzte Aktualisierung: 18.04.2013

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Abstract

Background: Serotoninergic transmission participates in numerous physiological and neurocognitive processes. The metabolism of serotonin (5-HT), including its multi-step interconversion into melatonin, involves several polymorphic enzymes (cytochrome P450 isoenzymes CYP2D6 and CYP1A2, and Arylalkylamine N-acetyl-transferase AA-NAT), which have been correlated with phenotypic traits affecting circadian rhythm, sleep, mood, diabetes, metabolic syndrome, as well as drug response and adverse drug reactions. To date no endogenous substrate is validated as test probe for phenotyping these enzymes. Beside its neuroregulatory functions, 5-HT is also produced physiologically by enterochromaffin cells and in pathological excess by a subset of gastrointestinal neuroendocrine tumors that cause “carcinoid syndrome”. 5-HT in platelets and its oxydated end-product 5-hydroxyindole acetic acid (5-HIAA) in urine are established markers for the diagnosis of the tumor and the monitoring of its treatment. However, 5-HT can also derive from dietary intakes of L-tryptophan, thus causing false-positive results (low specificity); conversely, endogenous 5-HT undergoes complex metabolism and transport that result in loose relationships between its secretion and those biomarkers (low sensitivity). Altogether, tests based on platelet 5-HT or 5-HIAA are mainly able to reveal a late diagnosis of metastatic carcinoid tumor.Working hypothesis: 5-HT and catecholamines share similarities regarding their physiological roles (signaling in nervous and gastro-intestinal systems), pathological sources (neuroendocrine tumors) and metabolism (oxidative deamination, O-methylation and sulphuric conjugation). The determination of native catecholamines or their terminal end-product (vanilylmandelic acid) in blood or urine had poor diagnostic performances for the identification and follow up of pheochromocytoma and neuroblastoma. Measuring intermediate metabolites (metanephrines) markedly improved the diagnosis and the monitoring of these catecholamine-secreting tumors. We hypothesize that the poor diagnostic value of 5-HT and 5-HIAA for carcinoid tumors is due to similar issues (specific intratumoral metabolism, variability in biotranformation steps leading to 5-HIAA), thus leaving room for improvement of tests based on intermediate metabolites. On the other hand, 5-HT and its intermediate metabolites are endogenous substrates of polymorphic enzymes and could be used to phenotype CYP2D6, CYP1A2 and AA-NAT without using exogenous drug probes. They might also reflect the actions of pharmaceutical modulators of serotoninergic transmission. Specific aims: This research aims to identify and develop new biomarkers for the diagnosis and follow up of carcinoid tumors, to investigate their sensitivity to specific drugs (both as nuisance for their diagnostic performance and as research tools to assess drug response to serotoninergic or antiserotoninergic agents), and to evaluate their potential as endogenous probes for the phenotyping of pharmacokinetic pathways of interest affected by both genetic polymorphisms and drug interactions. Methods and proposed studies: The Laboratory of Catecholamine and Peptides in Lausanne, an international leading center for pheochromocytoma and neuroblastoma diagnosis, will validate a highly sensitive and specific assay for 8 metabolites deriving from 5-HT, using tandem mass spectrometry with isotopic internal. Normal ranges will be established in healthy volunteers. Diagnostic performances for carcinoid tumors will be evaluated in a case-control trial. Observational and case crossover studies will assess the influence of specific drugs or conditions on these biomarkers. And a randomized clinical investigation will appraise their use as endogenous probe substrates for the phenotyping of CYP2D6, CYP1A2 and AA-NAT. Expected value of the proposed research: Beyond the native 5-HT and the end-product 5-HIAA, novel biomarkers derived from intermediate metabolites of 5-HT may allow earlier diagnosis and improved follow up of carcinoid tumors. Related biomarkers might also bring new convenient tools for the phenotyping of polymorphic enzymes involved in drug metabolism and for the clinical monitoring of serotoninergic or antiserotoninergic drug agents.
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