Open AccessSerotonin biosynthesis as a predictive marker of serotonin pharmacodynamics and disease-induced dysregulation
Author(s) -
Richard W. D. Welford,
Magali Vercauteren,
Annette Trébaul,
Christophe Cattaneo,
Doriane Eckert,
Marco Garzotti,
Patrick Sieber,
Jérôme Segrestaa,
R. O. Studer,
Peter M.A. Groenen,
Oliver Nayler
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep30059
Subject(s) - tryptophan hydroxylase , serotonin , pharmacodynamics , in vivo , endocrinology , medicine , tryptophan , pharmacology , chemistry , lung , pharmacokinetics , biology , biochemistry , serotonergic , amino acid , receptor , microbiology and biotechnology
The biogenic amine serotonin (5-HT) is a multi-faceted hormone that is synthesized from dietary tryptophan with the rate limiting step being catalyzed by the enzyme tryptophan hydroxylase (TPH). The therapeutic potential of peripheral 5-HT synthesis inhibitors has been demonstrated in a number of clinical and pre-clinical studies in diseases including carcinoid syndrome, lung fibrosis, ulcerative colitis and obesity. Due to the long half-life of 5-HT in blood and lung, changes in steady-state levels are slow to manifest themselves. Here, the administration of stable isotope labeled tryptophan (heavy “h-Trp”) and resultant in vivo conversion to h-5-HT is used to monitor 5-HT synthesis in rats. Dose responses for the blockade of h-5-HT appearance in blood with the TPH inhibitors L- para -chlorophenylalanine (30 and 100 mg/kg) and telotristat etiprate (6, 20 and 60 mg/kg), demonstrated that the method enables robust quantification of pharmacodynamic effects on a short time-scale, opening the possibility for rapid screening of TPH1 inhibitors in vivo . In the bleomycin-induced lung fibrosis rat model, the mechanism of lung 5-HT increase was investigated using a combination of synthesis and steady state 5-HT measurement. Elevated 5-HT synthesis measured in the injured lungs was an early predictor of disease induced increases in total 5-HT.