Disease relevance of Tph1

• Mice deficient in peripheral tryptophan hydroxylase (TPH1) and serotonin exhibit a reduced risk of thrombosis and thromboembolism [1].
• We have cloned the tryptophan hydroxylase cDNA from hamster pituitary and demonstrated its expression in the skin, melanotic and amelanotic melanomas, spleen, heart, and the eye [2].
• Characterization and chromosomal mapping of a cDNA encoding tryptophan hydroxylase from a mouse mastocytoma cell line [3].
• A 6.1 kb 5' upstream region of the mouse tryptophan hydroxylase gene directs expression of E. coli lacZ to major serotonergic brain regions and pineal gland in transgenic mice [4].
• Our goal is to utilize antagonists of the serotonin-producing enzymes (tryptophan hydroxylase and AADC) as the basis for a chemotherapeutic approach to the treatment of carcinoid tumors, a rare tumor type characterized by the overproduction of serotonin [5].

Psychiatry related information on Tph1

• Inhibition of tryptophan hydroxylase activity and decreased 5-HT1A receptor binding in a mouse model of Huntington's disease [6].

High impact information on Tph1

• Serotonin is synthesized independently in peripheral tissues and neurons by two different rate-limiting tryptophan hydroxylase (TPH) isoenzymes [7].
• Here, we show that mice selectively deficient in peripheral TPH and serotonin exhibit impaired hemostasis, resulting in a reduced risk of thrombosis and thromboembolism, although the ultrastructure of the platelets is not affected [7].
• Lowering brain 5-HT levels by administration of the selective tryptophan hydroxylase inhibitor p-chlorophenylalanine on postnatal days 0 and 1 restored the metabolic responses to functional activation in the whisker-to-barrel cortex pathway in adult 5-HTT(-/-) mice [8].
• Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism [9].
• These neuron-like cells differed from serotoninergic neurons in cultured embryonic mouse brain stem since they did not contain tryptophan hydroxylase [10].

Chemical compound and disease context of Tph1

• The carcinoid neoplasm is marked by excessive serotonin, synthesized by the conversion of tryptophan (Trp) to 5-hydroxytryptophan by tryptophan hydroxylase (TPH) (EC 1.14.16.4) and decarboxylation of 5-hydroxytryptophan by aromatic-L-amino acid decarboxylase (AAAD) (EC 4.1.1.28) [11].
• When the mice were given ethanol at an elevated environmental temperature (34 degrees C) the hypothermia was almost abolished completely, but depressant effects on TpH activity remained, suggesting that ethanol-induced decreases in TpH activity were direct effects and not secondary to hypothermia [12].
• The (R)- and (S)-enantiomers of salsolinol, the dopamine-derived tetrahydroisoquinolines, were found to inhibit the activity of tryptophan hydroxylase (TPH), prepared from serotonin-producing murine mastocytoma P-815 cells [13].
• Inhibition of tryptophan hydroxylase with p-chlorophenylalanine and p-chloromethamphetamine drastically decreased immobility time in hereditary predisposed to catalepsy animals [14].
• Unsuccessful attempts to reproduce the in vivo effects of MDMA on TPH activity using in vitro preparations such as cortical slices or the mouse mastocytoma cell line, P-815, suggested a requirement for an intact neuronal system or metabolism of the drug [15].

Biological context of Tph1

• We also demonstrated that this active tRNA-miniribozyme chimera is capable of selectively cleaving native Tph1 mRNA in vivo, with concomitant downregulation of the serotonin biosynthesis [1].
• Differential tissue distribution of tryptophan hydroxylase isoforms 1 and 2 as revealed with monospecific antibodies [16].
• TPH mRNA was elevated during pregnancy and lactation, and serotonin was detected in the mammary epithelium and in milk [17].
• The mouse tryptophan hydroxylase locus, termed Tph, was mapped by Southern blot analysis of somatic cell hybrids and by an interspecific backcross to a position in the proximal half of chromosome 7 [3].
• A cDNA library was constructed from RNA prepared from P815 mouse mastocytoma cells and screened for tryptophan hydroxylase [3].

Anatomical context of Tph1

• Estrogen receptor-beta regulates tryptophan hydroxylase-1 expression in the murine midbrain raphe [18].
• Gr B mediates the cytotoxic activity of mast cells, and TPH is a rate-limiting enzyme for the synthesis of serotonin [19].
• Hormonal effects on TPH2 mRNA expression in the rodent dorsal raphe nucleus (DRN) are unknown [20].
• BACKGROUND: Recently a novel tryptophan hydroxylase isoform (TPH2) was identified and shown to be highly expressed in the central nervous system (CNS) [20].
• A significant number of 5-HT (TpOH-positive) cell bodies and dendrites endowed with NK1r were thus demonstrated in the caudal part of rat and mouse DRN [21].

Associations of Tph1 with chemical compounds

• Tryptophan hydroxylase (TPH)-deficient (Tph1-/-) mice lack peripheral 5-HT [22].
• Tryptophan hydroxylase (TPH) is abundantly expressed in the serotonergic neurons of the DRN and is regulated by estrogen in both the monkey and the guinea pig [18].
• RESULTS: Dexamethasone reduced TPH2 mRNA levels in the DRN of both ovx female and intact male mice [20].
• Reduction of TPH2 mRNA in the DRN was blocked by co-administration of mifepristone [20].
• A specific antibody to tryptophan hydroxylase [L-tryptophan, tetrahydropteridine:oxygen oxidoreductase (5-hydroxylating), EC 1.14.16.4] has been used to localize the enzyme immunohistochemically in neurons of the mammalian gut [23].

Regulatory relationships of Tph1

• TPH was induced by PRL in mammosphere cultures and by milk stasis in nursing dams, suggesting that the gene is controlled by milk filling in the alveoli [17].
• The activity of tryptophan 5-monooxygenase was selectively enhanced 4.5-fold by the combination of IL-3 with KL [24].
• H13/04 was subsequently shown to competitively inhibit tryptophan hydroxylase [25].
• Here we investigated the effect of genetic deletion of tryptophan hydroxylase 1 on hypoxia-induced pulmonary arterial hypertension in mice by measuring pulmonary hemodynamics and pulmonary vascular remodeling before and after 2 weeks of hypoxia [26].

Other interactions of Tph1

• Because TPH is the rate-limiting enzyme for serotonin synthesis, we examined the serotonin content of +/+ and mi/mi CMCs [27].
• Dual-label immunocytochemistry was performed for PR or ER alpha and the serotonin-synthesizing enzyme, tryptophan hydroxylase (TPH) [28].
• The results support a link between the C1473G polymorphism in Tph2 gene, tryptophan hydroxylase activity and intensity of intermale aggression [29].
• In addition, RNase protection assays and immunohistochemical methods detected TPH mRNA and protein, respectively, confirming the endogeneous production of 5-HT in these cells [30].
• In consequence, the concerted action of IL-3 and KL on the GTP cyclohydrolase I and the tryptophan 5-monooxygenase reaction enhances the production of serotonin to about 20-fold levels [24].

Analytical, diagnostic and therapeutic context of Tph1

• Therefore, this Tph1-specific miniribozyme may provide a novel and effective form of gene therapy that may be applicable to a variety of thrombotic diseases [1].
• METHODS: In situ hybridization histochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) were used to assess the effects of dexamethasone or estradiol on TPH2 mRNA levels in the DRN of C57/Bl6 mice [20].
• As visualized by electron microscopy after gold immunolabelling, NK1r was mostly cytoplasmic in 5-HT neurons, while predominating on the plasma membrane in the case of TpOH-negative dendrites [21].
• By gene targeting, we have shown that serotonin is synthesized independently by two different tryptophan hydroxylase isoenzymes in peripheral tissues and neurons and identified a neuronal tryptophan hydroxylase isoform [1].
• In situ hybridization histochemistry revealed that there was a small but statistically significant decrease in TPH mRNA expression in the ventral DRN subdivision in betaERKO mice compared with betaWT mice, whereas TPH mRNA levels were not affected in alphaERKO mice [31].

References