The alteration of serotonin metabolism to 5-hydroxytryptophol by ethanol ingestion in man.
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5-Hydroxytryptophan↗
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[Respiration of rat cerebral cortex slices after addition of 5-hydroxytryptophol].
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Animals↗
Changes in serotonin metabolism during treatment with the aldehyde dehydrogenase inhibitors disulfiram and cyanamide.
The effect of the aldehyde dehydrogenase inhibitors disulfiram (Antabuse) and cyanamide (calcium carbimide, Dipsan) on the metabolism of serotonin measured as relative amounts of the metabolites 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol in urine were studied in alcoholic patients. Sixteen out of 23 patients receiving drug therapy showed elevated excretion of 5-hydroxytryptophol. However, there was a marked, 15-fold, variability in 5-hydroxytryptophol excretion rate between patients. A high degree of variability was also seen in another group of patients studied before and after introduction of drug therapy. When patients were followed during the dose interval, a time-dependent response after each single dose could be observed. The disulfiram response lasted over the course of several days whereas the response to cyanamide lasted for less than 12 hr. It is concluded that treatment with disulfiram and cyanamide affects serotonin metabolism leading to increased production of 5-hydroxytryptophol, but there is a marked inter-individual variability in degree of response.
Adult↗
Antioxidative and free radical scavenging activities of pineal indoles.
The antioxidant action, free radical scavenging activity and pro-oxidant effect of pineal indoles were studied. Serotonin, 5-hydroxytryptophol, 5-methoxytryptophol and 5-methoxytryptamine potently inhibited lipid peroxidation in rat brain, liver and kidney homogenates and hemolysis of rat erythrocytes. 5-Methoxyindole-3-acetic acid and 5-hydroxyindole-3-acetic acid potently suppressed superoxide radical formation. 5-Hydroxytryptophol and 5-hydroxyindole-3-acetic acid inhibited hydroxyl radical generation. Serotonin, 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid exhibited a pro-oxidant action in the bleomycin-Fe system. This study demonstrated that 5-methoxytryptamine, among the various pineal indoles tested, exhibited the most potent antioxidant action and was devoid of pro-oxidant effect. Serotonin, 5-hydroxytryptophol and 5-methoxytryptophol also had high antioxidative activity. By comparison melatonin had a lower antioxidant potency.
Animals↗
Effect of 5-hydroxytryptamine and pineal metabolites on the secretion of neurohypophysial hormones.
It has been shown that 5-hydroxytryptamine and melatonin, an indoleamine for which 5-hydroxytryptamine is a precursor, influence the release of vasopressin and oxytocin from the rat hypothalamus both in vivo and in vitro. The oral administration of melatonin has been shown to decrease oxytocin release and modulate the nocturnal vasopressin release in humans. 5-hydroxytryptamine and its metabolites, 5-hydroxytryptophol, 5-methoxytryptamine and 5-methoxytryptophol, are detected within the pineal, and there is evidence that 5-methoxytryptamine and 5-methoxytryptophol may have some physiological role. The aim of this study was to evaluate the effects of 5-hydroxytryptamine, 5-hydroxytryptophol, 5-methoxytryptamine and 5-methoxytryptophol on neurohypophysial hormone release from the rat hypothalamus in vitro. It was found that 5-hydroxytryptamine and 5-hydroxytryptophol increased neurohypophysial hormone release, 5-methoxytryptamine decreased the release of vasopressin and oxytocin and 5-methoxytryptophol was found to have no effect, thus providing further evidence for a role of indole compounds in the control of neurohypophysial hormone secretion.
5-Methoxytryptamine↗
Examination of pineal indoles and 6-methoxy-2-benzoxazolinone for antioxidant and antimicrobial effects.
Oxidative modification of low density lipoprotein (LDL) induced by free radicals is implicated in the development of atherosclerosis. The aim of the present study was to examine the ability of various pineal indoles in inhibiting LDL oxidation which is accompanied by an increase in mobility in agarose gel electrophoresis and by an augmented generation of thiobarbituric acid-reactive substance induced by Cu2+. It was found that the order of potencies in inhibiting malondialdehyde formation was 5-hydroxytryptamine (serotonin)>5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid when tested at 4 mM. 5-methoxytryptamine was as effective as 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid when tested at 4 mM but was inactive at 1 mM. 5-methoxytryptophol was marginally active at 4 mM. Melatonin, 5-methoxyindole-3-acetic acid and 6-methoxy-2-benzoxazolinone were inactive even at 4 mM. The ranking of antioxidative potencies as reflected in the shift of mobility in agar gel electrophoresis was 5-hydroxytryptamine>5-methoxytryptamine>5-hydroxyindole-3-acetic acid and 5-methoxytryptophol>5-hydroxytryptophol and melatonin. Another aim of this investigation was to ascertain the action of the aforementioned pineal indoles on the enhanced lipid peroxidation brought about in the mouse kidney and liver by intraperitoneal administrations of carbon tetrachloride. It was found that all pineal indoles tested demonstrated an inhibitory effect in the kidney but not in the liver. 6-methox-2-benzoxazolinone and 5-methoxyindole-3-acetic acid exerted antifungal activity against Mycosphaerella arachidicola, Botrytis cinerea and Physalospora piricola. 6-methoxy-2-benzoxazolinone exhibited antibacterial activity against Proteus vulgaris and 5-methoxytryptamine against Staphylocccus aureus and Bacillus subtilis. Other pineal indoles did not possess antifungal or antibacterial action.
Animals↗
Concentration of serotonin metabolites in the cerebrospinal fluid from alcoholics before and during disulfiram therapy.
The levels of 5-hydroxytryptophol and 5-hydroxyindoleacetic acid were measured in the cerebrospinal fluid before and after one week of disulfiram treatment (400 mg/day) from ten male hospitalized alcoholic patients. The disulfiram treatment induced elevated (P less than 0.001) levels of 5-hydroxytryptophol. The levels were higher than in a control group, both before (P less than 0.01) and after (P less than 0.001) the treatment. No effects on the levels of 5-hydroxyindoleacetic acid were noted. The results indicate an altered serotonin metabolism in alcoholics, which is further potentiated by disulfiram treatment.
Alcoholism↗
Metabolism of platelet 5-hydroxytryptamine in acidified platelet concentrates.
The present study was designed to understand the metabolism of 5-hydroxytryptamine (serotonin, 5HT), a dense granule constituent of platelets, in acidified platelet concentrates (PC) during in vitro storage in polyvinylchloride plastic containers at 22 degrees C. High-performance liquid chromatographic analysis showed that significant amounts of 5HT and its metabolites, 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid (5HIAA), were detected in the plasma of all PC stored for 3 days with a pH below 6.0, measured at 37 degrees C. PC with a platelet number over 7 x 10(10) cells maintained low PO2 values. Rapid fall in pH occurred in these PC with low PO2 values. The rate of lactate production of platelets increased several fold because of an insufficient oxygen supply to them. In PC with a sufficient supply of oxygen, the adenosine triphosphate (ATP) production rates were estimated to be 8 nmol/min/10(9) platelets. In PC acidified below pH 6.0, the oxidative phosphorylation nearly ceased, and glycolysis was also inhibited: ATP production rates averaged 1 nmol/min/10(9) platelets at 3-day storage. Numerous clusters of platelet aggregates were found in acidified PC, and platelets changed into spherical shapes with accompanying swelling. These platelets did not respond to adenosine triphosphate and failed to produce shrinking when suspended in hypotonic solutions. 5HT was not metabolized in acidified platelet-poor plasma. These data suggest that the metabolic activity of platelets was impaired when the pH of the PC fell below 6.0, leading to the release of platelet 5HT into the plasma. A substantial amount of 5HT might be metabolized by platelet monoamine oxidase into 5HIAA and 5-hydroxytryptophol.
Blood Platelets↗
Age-related changes of serotonin and its metabolites content in the visual system of the rat.
Measurements have been taken of the serotonin and its metabolites (tryptophan, 5-hydroxytryptophan, 5-hydroxy-3-indolacetic acid and 5-hydroxytryptophol) in each structure of the geniculate and extrageniculate visual system of rats aged between 3 and 30 months. The concentration of tryptophan was the highest of all compounds studied. Its increase during ageing is statistically significant in the lateral geniculate and posterior thalamus. 5-HTP concentration was very low and in some cases not detectable. 5-HT concentrations and its principal metabolite, 5-HIAA, showed a different profile in each brain structure. The lateral geniculate and visual cortex showed statistically significant changes, but with opposite results. In the lateral geniculate the 5-HT and 5-HIAA concentrations were increased during the ageing period. However, in the visual cortex the 5-HT and 5-HIAA concentrations decreased in the same period. These age-related changes were not seen in the superior colliculus and posterior thalamus as in the 5-HT levels as in the 5-HIAA. 5-hydroxytryptophol was always found in low concentration. These results suggest age-related changes in the geniculate visual system.
Aging↗
Determination of melatonin and monoamines in rat pineal using reversed-phase ion-interaction chromatography with fluorescence detection.
A method is reported for the ion-interaction, reversed-phase separation of 24 compounds (chiefly monoamines) arising from the metabolism of tyrosine and tryptophan. These compounds were separated as two groups. The first group comprised 3,4-dihydroxyphenylethylene glycol, tyrosine, 3-methoxy-4-hydroxyphenyl glycol, 5-hydroxytryptophan, norepinephrine, 3,4-dihydroxyphenylacetic acid, epinephrine, 5-hydroxyindole-3-acetic acid, homovanillic acid, 5-hydroxytryptophol, dopamine, tryptophan. N-acetylserotonin, N-acetyltryptophan, 5-methoxytryptophan and serotonin. The mobile phase consisted of a 6.8:93.2 (v/v) mixture of acetonitrile and an aqueous solution containing 0.16 M ammonium phosphate, 0.06 M citric acid, 0.15 mM disodium EDTA, 10 mM dibutylamine and 6 mM sodium 1-octanesulphonate at pH 4.50. The second group of compounds comprised 6-hydroxymelatonin, 5-methoxyindole-3-acetic acid, indole-3-acetic acid, 5-methoxytryptamine, tryptamine, 5-methoxytryptophol, melatonin and tryptophol. The mobile phase consisted of a 16:84 (v/v) mixture of acetonitrile and an aqueous solution containing 0.05 M ammonium phosphate, 0.05 M citric acid, 0.15 mM disodium EDTA, 25 mM dibutylamine and 5 mM sodium 1-octanesulphonate at pH 5.30. Detection was by fluorescence measurement (lambda ex = 280 nm, lambda em = 340 nm). The proposed method exhibited linear calibration over the biochemically significant concentration range, with detection limits in the 10-200 pg range. Excellent precision for peak areas and retention times was observed, even over a period of 24 h. The applicability of amperometric detection (at 0.72V) is also demonstrated. The method is applied to the determination of monoamines in individual rat pineals. Low nanogram levels of tyrosine, norepinephrine, 5-hydroxyindole-3-acetic acid, tryptophan, serotonin and 6-hydroxymelatonin, and picogram levels of 5-hydroxytryptophan, 5-hydroxytryptophol, 5-methoxyindole-3-acetic acid, indole 3-acetic acid, 5-methoxytryptophol and melatonin were indicated in most of the samples.
Animals↗
In vitro uptake and metabolism of [3H]indole compounds in the pineal organ of the pike. I. A radiochromatographic study.
Thin layer chromatography analysis of [3H]serotonin and [3H]melatonin metabolites synthetized in vitro by the pineal organ of the pike was performed. After a 10-min pulse, [3H]serotonin was mainly converted into [3H]-5-hydroxyindoleacetic acid (37%), [3H]-5-hydroxytryptophan and [3H]-5-methoxytryptophan (12 to 14%), and [3H]-5-hydroxytryptophol and [3H]-5-methoxytryptophol (3.5 and 9%) at the onset of darkness. When the pulse was followed by postincubations (in a cold medium) of increasing duration (15, 30, and 60 min), it appeared that the amount of [3H]-5-hydroxyindoleacetic acid decreased, that of [3H]-5-hydroxytryptophol decreased faster than that of [3H]-5-methoxytryptophol, and the amounts of [3H]-5-hydroxy- and [3H]-5-methoxytryptophan increased. [3H]-N-acetylserotonin, [3H]melatonin, and [3H]-5-methoxytryptamine were found in very low amounts. At the beginning of the photophase or at the onset of darkness, the uptake and metabolism of [3H]melatonin (after a 10-min pulse followed by a 10-min incubation in cold medium) resulted mainly in the formation of [3H]-5-methoxytryptophol (23 to 43%) and of [3H]-5-methoxytryptamine (6 to 12%). These results show that the pike pineal organ can synthesize all indoles that are known in the pineal gland of higher vertebrates. Usual, but also unusual, pathways of the indole metabolism were found that will need further clarification. Among these are the possible carboxylation of serotonin and deacetylation of melatonin (leading to the synthesis of 5-methoxytryptophol). Altogether, the results obtained suggest that the indole metabolism might be more complex than what has already been described in vertebrates.
Animals↗
Effects of pineal indoles and arginine vasotocin on lipolysis and lipogenesis in isolated adipocytes.
The effects of arginine vasotocin and the pineal indoles melatonin, serotonin, N-acetylserotonin, hydroxytryptophol, methoxytryptophol, hydroxyindoleacetic acid, methoxyindoleacetic acid, and methoxytryptamine on lipolysis and lipogenesis in isolated adipocytes were studied. Basal lipolysis was inhibited by all the indoles tested at a dose of 1 mumole except hydroxytryptophol. Methoxytryptamine and serotonin inhibited hormone-induced lipolysis in a dose-dependent manner and exhibited the highest antilipolytic activity in isolated rat, rabbit, and hamster adipocytes. However, their antilipolytic activity could not be overcome by increasing the dose of the lipolytic hormone. Dibutyryl cyclic AMP-induced lipolysis was also inhibited. All the pineal indoles tested were capable of suppressing basal and insulin-stimulated lipogenesis in the dose range 0.33-3 nmole. At lower doses there was no effect. Arginine vasotocin at a dose of 25 nmole significantly augmented basal lipogenesis.
Adipose Tissue↗
Diurnal changes in cyclic nucleotide response to pineal indoles in murine mammary glands.
The aim of this study was to determine whether pineal indoles affect cyclic nucleotide levels in mammary gland slices of BALB/c adult mice. Melatonin at 0.1 nM-10 microM concentrations decreased cAMP and augmented cGMP concentration in murine mammary gland slices in the presence of a phosphodiesterase inhibitor (1 mM theophylline), an index of cyclic nucleotide synthesis. Melatonin-induced changes in cyclic nucleotide levels were significantly larger at the end of the light period (2000) than in the morning (at 1000). Indole-induced inhibition of cyclic AMP levels by mammary slices exhibited the following order of potency: 5-methoxytryptamine > melatonin > or = 6-hydroxymelatonin > serotonin, N-acetylserotonin > 5-hydroxytryptophol. The order of potency for indole-induced augmentation of cyclic GMP levels was: 5-methoxytryptamine > melatonin > 6-hydroxymelatonin > serotonin, N-acetylserotonin, 5-hydroxytryptophol. When melatonin or 5-methoxytryptamine (10 nM) were examined for their effects on cAMP and cGMP levels in mammary glands of mice killed at six different time intervals during the 24-hr cycle, the activity was maximal during night. The data demonstrate that 5-methoxytryptamine and melatonin decreased cAMP and increased cGMP levels in mammary gland slices. Methoxyindole-induced changes in cyclic nucleotide synthesis in murine mammary glands exhibit the time-dependency known to occur in several other melatonin-influenced responses.
Animals↗
INDOLE COMPOUNDS: ISOLATION FROM PINEAL TISSUE.
Five indole compounds have been isolated from bovine pineal tissue and characterized as 5-methoxytryptophol, N-acetyl-5-methoxytryptamine (melatonin), 5-hydroxytryptophol, 5-methoxyindole-3-acetic acid, and 5-hydroxyindole-3-acetic acid. Pineal hydroxyindole-O-methyltransferase, with S-adenosylmethionine, converts 5-hydroxytryptophol to 5-methoxytryptophol.
Animals↗
Brain receptors sensitive to indole compounds: function in control of luteinizing hormone secretion.
The placement of melatonin and of 5-hydroxytryptophol in the median eminence of castrated male rats is followed 5 days later by a significant decrease in pituitary stores of luteinizing hormone. Pituitary reserve of this hormone is also depleted after the implantation of melatonin, 5-hydroxytryptophol, and 5-methoxytryptophol in the reticular formation of the midbrain. It is suggested that these indole compounds, which are normally synthesized in the pineal gland, may intervene in the control of the secretion of luteinizing hormone, possibly by acting on specific receptors localized in the median eminence and in the midbrain.
Animals↗
Reciprocal day/night relationship between serotonin oxidation and N-acetylation products in the rat pineal gland.
Pineal tryptophan, serotonin [5-hydroxytryptamine (5-HT)], N-acetylserotonin, melatonin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-methoxytryptophol, and 5-methoxyindoleacetic acid were measured by high pressure liquid chromatography with electrochemical detection. A complete analysis required less than the equivalent of two rat pineal glands. Samples were obtained at eight time points. A reciprocal physiological relationship was found between oxidation and N-acetylation products of 5-HT. 5-HT and the oxidation products 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-methoxytryptophol, and 5-methoxyindoleacetic acid decreased at night, when the N-acetylation products N-acetylserotonin and melatonin increased. These observations are consistent with the hypothesis that circadian changes in the N-acetylation of 5-HT by indoleamine N-acetyltransferase is the major factor controlling circadian changes in the amounts of 5-HT, and 5-HT oxidation and N-acetylation products in the rat pineal gland.
Acetylation↗
Production and metabolism of serotonin (5-HT) by the human adrenal cortex: paracrine stimulation of aldosterone secretion by 5-HT.
In the human adrenal cortex, serotonin (5-HT) is contained in mast-like cells, and we have shown that 5-HT stimulates aldosterone secretion, suggesting that 5-HT may control glomerulosa cells through a paracrine mechanism. Concurrently, the presence of 5-hydroxyindolacetic acid in human adrenocortical extracts indicates that 5-HT may be metabolized after local release by mast cells. The aim of the present study was to investigate in vitro the production and metabolism of 5-HT by the human adrenal cortex. Perifused adrenal slices released spontaneously detectable amounts of 5-HT (0.74 +/- 0.38 fmol/mg wet tissue.min). The mast cell-depleting drug compound 48/80 induced a burst of 5-HT secretion followed by a gradual increase in aldosterone production. Administration of the specific 5-HT(4) receptor antagonist GR 113808 (10(-6) M) did not affect compound 48/80-induced 5-HT release but abolished the stimulatory effect of compound 48/80 on aldosterone secretion, indicating that 5-HT released locally is responsible for a paracrine control of steroidogenesis. Incubation of cells from the human adrenal cortex with 5-HT (10(-5) M) provoked the formation of the 5-HT metabolite 5-hydroxytryptophol. The type A monoamine oxidase (MAO) inhibitor clorgyline (10(-6) M) suppressed the metabolism of 5-HT into 5-hydroxytryptophol. Immunocytochemical staining of cultured cells revealed the presence of a subpopulation of MAO-A-positive cells. Double labeling with an antiserum against chromogranin A showed that MAO-A was actually contained in chromaffin cells. Similarly, immunohistochemical staining of adrenal slices showed that MAO-A was expressed in chromaffin cells located both in the medulla and in intracortical rays. In conclusion, the present study shows that, in the human adrenal cortex, 5-HT, released by mast-cells, may stimulate aldosterone secretion in a paracrine manner. Our data also indicate that 5-HT is metabolized by MAO-A located in intracortical chromaffin cells.
Adrenal Cortex↗
Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites.
The purpose of the present study was to elucidate the expression of human organic anion transporter 1 (hOAT1) and hOAT3 in the choroid plexus of the human brain and their interactions with neurotransmitter metabolites using stable cell lines. Immunohistochemical analysis revealed that hOAT1 and hOAT3 are expressed in the cytoplasmic membrane and cytoplasm of human choroid plexus. Neurotransmitter metabolites, namely, 5-methoxyindole-3-acetic acid (5-MI-3-AA), homovanillic acid (HVA), vanilmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindole-3-acetic acid (5-HI-3-AA), N-acetyl-5-hydroxytryptamine (NA-5-HTT), melatonin, 5-methoxytryptamine (5-MTT), 3,4-dihidroxymandelic acid (DHMA), 5-hydroxytryptophol, and 5-methoxytryptophol (5-MTP), but not methanephrine (MN), normethanephrine (NMN), and 3-methyltyramine (3-MT), at 2 mM, inhibited para-aminohippuric acid uptake mediated by hOAT1. On the other hand, melatonin, 5-MI-3-AA, NA-5-HTT, 5-MTT, 5-MTP, HVA, 5-HI-3-AA, VMA, DOPAC, 5-hydroxytryptophol, and MN, but not 3-MT, DHMA, and NMN, at 2 mM, inhibited estrone sulfate uptake mediated by hOAT3. Differences in the IC(50) values between hOAT1 and hOAT3 were observed for DHMA, DOPAC, HVA, 5-HI-3-AA, melatonin, 5-MI-3-AA, 5-MTP, 5-MTT, and VMA. HOAT1 and hOAT3 mediated the transport of VMA but not HVA and melatonin. These results suggest that hOAT1 and hOAT3 are involved in the efflux of various neurotransmitter metabolites from the cerebrospinal fluid to the blood across the choroid plexus.
Cell Line↗