5-Hydroxytryptophan (5-HTP)-induced intracellular syndrome in mouse non-neural embryonic cells is associated with inhibited proliferation and cell death. (1st September 2021)

• Record Type: Journal Article
• Authors: Gordeeva, Olga; Safandeev, Vitaliy
• Is Part Of: Neuropharmacology. Volume 195(2021)
• Publication Date: 2021-09-01
• Subjects: 5-HTP -- Serotonin -- Cytotoxicity -- Embryonic stem cells -- Proliferation -- Cell death; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107862
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Biogenic monoamines are involved in the regulation of various processes in both neural and non-neural cells during development. The present study aimed to identify the regulatory effects of serotonin (5-HT) and its precursors (l -tryptophan and 5-hydroxytryptophan, 5-HTP) on proliferation and cell death in mouse embryonic stem cells (ESCs) and embryonic fibroblasts (MEFs and 3T3 cells). The concentration-dependent cell growth and viability of the ESCs, MEFs and 3T3 cells were analyzed after treatment with l -tryptophan, 5-HTP and 5-HT in the concentration range 10 −6 - 10 −2 M. Treating the cells with 5-HTP, but not l -tryptophan and 5-HT, induced reversible toxic effects. 5-HTP treatment (10 −3 - 10 −2 M) significantly inhibited cell proliferation through blocking of the S-phase of the cell cycle and increasing apoptotic and necrotic cell death. Moreover, 5-HTP treatment stimulated a reorganization of the actin and tubulin networks and upregulated the gene expression of enzymes involved in 5-HT synthesis and metabolism: aromatic amino acid decarboxylase ( Aadc/Ddc), monoamine oxidase A ( Maoa), and transglutaminase 2 ( Tgm2) . HPLC analysis found no changes in the intracellular and extracellular levels of 5-HT after 5-HTP treatment, but a significant increase of intracellular 5-HTP levels. However, inhibition of AADC with NSD-1015 or transglutaminase with cystamine prevented 5-HTP-induced cell growth impairment and attenuated the toxic effects of 5-HTP treatment. Our results suggest that 5-HTP can induce toxic effects through cell cycle arrest and cell death in embryonic stem and somatic cells by enhancing the levels of 5-HT-mediated protein modifications. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'. Highlights: 5-HTP at high doses induces reversible toxic effects in non-neural embryonic cells. 5-HTP inhibits cell proliferation and stimulates cell death and cytoskeleton alterations. 5-HTP treatment enhances its intracellular level and Aadc, Maoa and Tgm2 expression. Inhibition of AADC and TG prevents 5-HTP toxic effects and rescues cell growth. Protein serotonylation is a potential mechanism of 5-HTP-induced toxicity.