<i>p</i>‐Ethynylphenylalanine

Stokes, Alan H.; Xu, Yimei; Daunais, James A.; Tamir, Hadassah; Gershon, Michael D.; Butkerait, Paul; Kayser, Bernd; Altman, J.; Beck, Wolfgang; Vrana, Kent E.

doi:10.1046/j.1471-4159.2000.0742067.x

Cited by 20 publications

(4 citation statements)

References 34 publications

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Section: Discussionsupporting

confidence: 57%

“…The present in vitro assays suggested that QN competes directly with tryptophan for binding to the active site of TPH2, similar to the known competitive TPH2 inhibitor, pCPA31. pCPA potently decreases serotonin production in the brain31. The inference that QN, similarly, may have the potential to suppress serotonin production by cells was borne out by analysis of serotonin levels in RN46A cells and, in particular, yeast cells.…”

Section: Discussionmentioning

confidence: 54%

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The antimalarial drug quinine interferes with serotonin biosynthesis and action

Islahudin

Tindall

Mellor

et al. 2014

Sci Rep

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The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 54%

The antimalarial drug quinine interferes with serotonin biosynthesis and action

Islahudin

Tindall

Mellor

et al. 2014

Sci Rep

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“…This drug has not been studied extensively in humans, but it was found to reduce urinary excretion of 5-HIAA and the emetic response in chemotherapy patients [19]. Other methods to decrease levels of 5-HT, like using 6-fluorotryptophan, 5,7-dihydroxytryptamine, or creating lesions in the raphe nucleus have had limited success in animal models [20]. P-ethynylpheny-lalanine is a newer irreversible inhibitor of tryptophan hydroxylase, which was found to be more potent and more specific to tryptophan hydroxylase than pCPA.…”

Section: Discussionmentioning

confidence: 99%

“…P-ethynylpheny-lalanine is a newer irreversible inhibitor of tryptophan hydroxylase, which was found to be more potent and more specific to tryptophan hydroxylase than pCPA. However, this drug has not been studied in humans [20,21]. …”

Section: Discussionmentioning

confidence: 99%

De novo microdeletion of Xp11.3 exclusively encompassing the monoamine oxidase A and B genes in a male infant with episodic hypotonia: A genomics approach to personalized medicine

O’Leary

Shih

Hyland³

et al. 2012

European Journal of Medical Genetics

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Monoamine oxidase A and B (MAOA and MAOB) play key roles in deaminating neurotransmitters and various other biogenic amines. Patients deficient in one or both enzymes have distinct metabolic and neurologic profiles. MAOB deficient patients exhibit normal clinical characteristics and behavior, while MAOA deficient patients have borderline intellectual deficiency and impaired impulse control. Patients who lack both MAOA and MAOB have the most extreme laboratory values (urine, blood, and CSF serotonin 4–6 times normal, with elevated O-methylated amine metabolites and reduced deaminated metabolites) in addition to severe intellectual deficiency and behavioral problems. Mice lacking maoa and moab exhibit decreased proliferation of neural stem cells beginning in late gestation and persisting into adulthood These mice show significantly increased monoamine levels, particularly serotonin, as well as anxiety-like behaviors as adults, suggesting that brain maturation in late embryonic development is adversely affected by elevated serotonin levels. We report the case of a male infant with a de novo Xp11.3 microdeletion exclusively encompassing the MAOA and MAOB genes. This newly recognized X-linked disorder is characterized by severe intellectual disability and unusual episodes of hypotonia, which resemble atonic seizures, but have no EEG correlate. A customized low dietary amine diet was implemented in an attempt to prevent the cardiovascular complications that can result from the excessive intake of these compounds. This is the second report of this deletion and the first attempt to maintain the patient’s cardiovascular health through dietary manipulation. Even though a diet low in tyramine, phenylethylamine, and dopa/dopamine is necessary for long-term management, it will not rescue the abnormal monoamine profile seen in combined MAOA and MAOB deficiency. Our patient displays markedly elevated levels of serotonin in blood, serum, urine, and CSF while on this diet. Serotonin biosynthesis inhibitors like para-chlorophenylalanine and p-ethynylphenylalanine may be needed to lower serotonin levels in patients with absent monoamine oxidase enzymes.

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How applicable is the general adaptation syndrome to the unicellular Tetrahymena?

Csaba

Pállinger

2008

Cell Biochemistry & Function

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Hormone receptors, hormones and signal transduction pathways characteristic of higher vertebrates can be observed also in the unicellular Tetrahymena. Previous work showed that stress conditions (starvation, high temperature, high salt concentration, formaldehyde or alcohol treatment) elevated the intracellular level of four hormones (ACTH, endorphin, serotonin and T 3 ). Here, the effect of other stressors (CuSO4 poisoning, tryptophan hydroxylase inhibitor parachlorphenylalanine (PCPA) treatment) on the same and other hormones (epinephrine, insulin, histamine) was studied, using immunocytochemistry and flow cytometric analysis. It was found, that each effect increased the intracellular hormone contents, but some hormones (histamine, T 3 ) were less reactive. Insulin-which is a life-saving factor for Tetrahymena-itself provoked elevation of hormone amounts in association with a stressor, further increased the level of hormones. It was concluded that the ancestor of Selye's General Adaptation Syndrome (GAS) can be found already at unicellular level, and this possibly has a life saving function. Copyright # 2008 John Wiley & Sons, Ltd.key words -hormones; stress; general adaptation syndrome; GAS; Tetrahymena pyriformis INTRODUCTIONIt was demonstrated more than 30 years ago that the unicellular ciliate, Tetrahymena has binding sites (receptors) for hormones characteristic of higher ranked multicellular animals [1][2][3][4][5][6] and it also contains these hormones. 7-10 Some of these receptors are similar to those of the mammalian ones 10-14 and the hormones are not only cytochemically but also functionally similar to the hormones of mammals. 15The signal transduction pathways also can be found. [16][17][18] The hormones can transmit information within the Tetrahymena population even if they are present in an extremely small concentration. 19In earlier experiments it was demonstrated that stress conditions stimulate hormone production by Tetrahymena. Thermal or osmotic stress as well as starvation increased the cells' hormone (ACTH, endorphin, triiodothyronone (T 3 ) and serotonin) concentration, [20][21][22] suggesting that the General Adaptation Syndrome (GAS) of Selye 23 can be applied at a unicellular level. However, it was not clear how broad is the spectrum of hormones which are activated by stress, especially for epinephrine, which is a key-hormone in mammalian GAS, and whether insulin, which is a life-saving factor for Tetrahymena is also involved or not? In the present experiments we decided to study this problem. In addition the effect of other stressors and the effect of a stressor þ insulin combination are studied here, for testing the generality of GAS theory in unicellular organisms. MATERIALS AND METHODS Cells and culturingTetrahymena pyriformis GL strain was used in the logarithmic phase of growth. The cells were cultured at 288C in tryptone medium (Sigma, St. Louis, USA) containing 0.1% yeast extract, for 24 h. The density of Tetrahymena cultures studied was 10 4 cell mL À1 . TreatmentsStudy of osm...

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p‐Ethynylphenylalanine

Cited by 20 publications

References 34 publications

The antimalarial drug quinine interferes with serotonin biosynthesis and action

The antimalarial drug quinine interferes with serotonin biosynthesis and action

De novo microdeletion of Xp11.3 exclusively encompassing the monoamine oxidase A and B genes in a male infant with episodic hypotonia: A genomics approach to personalized medicine

How applicable is the general adaptation syndrome to the unicellular Tetrahymena?

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