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PubMed1993

Biogenic-amine acetylation: an additional function of the N-acetyltransferase from Fasciola hepatica.

The previously described polyamine N-acetyltransferase from Fasciola hepatica has been observed to have an additional function, the acetylation of biogenic amines. The activities for biogenic amines, diamines and polyamines were in a constant ratio throughout the purification process. Biogenic amines found to be substrates for the enzyme included tyramine, tryptamine, beta-phenylethylamine and histamine, with Km values of 0.12 mM, 0.26 mM, 0.30 mM and 0.76 mM respectively. Octopamine, 5-hydroxytryptamine and alpha-phenylethylamine were also acceptable as substrates, though to a lesser degree. The optimum pH for biogenic-amine acetylation was 7.5, and CoA was inhibitory to the process, with a Ki of 5.5 microM. N-Acetylation appears to play a major role in the amine metabolism of this trematode. We presume that acetylation represents the process by which the parasite inactivates excess amines.

Acetylation↗
PubMed1994

DNA strand cleavage as a sensitive assay for the production of hydroxyl radicals by microsomes: role of cytochrome P4502E1 in the increased activity after ethanol treatment.

There is increasing interest in the role of reactive oxygen radicals in the hepatotoxicity associated with ethanol consumption. Reactive oxygen intermediates interact with DNA and can cause single-strand breaks of supercoiled DNA. Experiments were carried out to evaluate the utility of this system as a sensitive assay for the detection of potent oxidants generated by rat liver microsomes isolated from pair-fed control rats and rats treated chronically with ethanol. DNA strand cleavage was assayed by monitoring the migration of the supercoiled and open circular forms in agarose. Microsomes catalysed DNA strand breakage with either NADPH or NADH as cofactors; iron was required to catalyse the reaction and various ferric complexes were effective in promoting the reaction. DNA strand cleavage was prevented by catalase, superoxide dismutase, GSH and hydroxyl-radical-scavenging agents, suggesting that a hydroxyl-radical-like species was the oxidant responsible for the breakage. This assay system proved to be much more sensitive in detecting hydroxyl radicals than are other methods, such as e.s.r. spectroscopy or oxidation of chemical scavenging agents with respect to the amount of microsomal protein and the nature and concentration of the iron catalyst required. Microsomes from ethanol-treated rats were more reactive than control microsomes in catalysing the DNA strand cleavage with either NADPH or NADH; increased catalytic activity was observed with various ferric complexes and was sensitive to the above antioxidants. Compared with preimmune IgG, anti-(cytochrome P4502E1) IgG had no effect on DNA strand cleavage by the control microsomes, but completely prevented the NADPH- and the NADH-dependent increased activity found with microsomes from the ethanol-treated rats. Inhibitors of cytochrome P4502E1, such as diethyl dithiocarbamate and tryptamine, also lowered the extent of increase of DNA strand cleavage produced by microsomes from the ethanol-treated rats. These results indicate that DNA strand cleavage is a very sensitive assay for detecting the production of hydroxyl radicals by microsomes and to demonstrate increased activity by microsomes after chronic ethanol treatment. This increased activity with NADPH and NADH is due, at least in part, to induction of cytochrome P4502E1.

Animals↗
PubMed2004

Further characterization of pigment-producing Malassezia strains.

Reference as well as field strains of Malassezia furfur (30), M. sympodialis (49), M. globosa (52), M. obtusa (one), M. restricta (one), M. slooffiae (seven), and M. pachydermatis (373) were investigated for their ability to produce pigment and fluorochromes when tryptophan (Trp) is offered as the main nitrogen source. Only the M. furfur strains produced pigment on a pigment-inducing medium (p-medium). Remarkably, the optical activity of Trp was not significant for pigment synthesis. Other nitrogen sources that are structurally similar to Trp (gramine, tryptamine, serotonin) did not induce pigment formation. All lipophilic non-furfur species failed to grow and to form pigment on this agar. However, growth of all lipid-dependent species was achieved on a modified Dixon agar in which peptone had been substituted by an equal amount of l-Trp. Here, too, the M. furfur colonies were characterized by rapidly developing dark brown halos. Furthermore, about 11% of the M. pachydermatis strains tested produced pigment formation on the p-medium, which was enhanced by addition of d-glucose. In contrast to M. furfur, pigment formation occurred after a markedly longer incubation time (4 weeks unlike 3-5 days) with a lower yield and limited color spectrum (thin layer chromatography, TLC). The UV filter pityriacitrine recently described for M. furfur was also demonstrated for M. pachydermatis by extraction, high-performance liquid chromatography (HPLC) analysis with co-elution and mass spectroscopy. The phenotypic feature of pigment formation in some strains of M. pachydermatis may confirm recent molecular-genetic findings suggesting a relationship between some strains of M. pachydermatis and M. furfur.

Alkaloids↗
PubMed2003

Functional study of rat 5-HT2A receptors using antisense oligonucleotides.

We studied the effects in rats of a 6-day intracerebroventricular (i.c.v) infusion of four different end-capped phosphorothioate-modified antisense oligonucleotides (AOs), specifically targeting different regions of the 5-hydroxytryptamine2A (5-HT2A) receptor mRNA, on central 5-HT2A receptor expression and 5-HT2A receptor-mediated behaviours. Only one of the AOs (sequence 4), directed against the 5'-untranslated region (from + 557 to + 577), specifically affected central 5-HT2A receptor expression and receptor-mediated behaviour. This AO (sequence 4) reduced binding of the 5-HT2A agonist 1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane ([125I]DOI) up to 25% in cortical areas, as measured by quantitative autoradiography. Cortical binding of the antagonist [3H]ketanserin was not affected. As the specific AO treatment presumably affects the synthesis of new receptor, we hypothesize that this newly synthesized receptor represents the major part of the functionally active, G protein coupled receptor. A 5-day infusion of AO (sequence 4) resulted in profound inhibition of the head-twitch response (HTR) to 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). In contrast, treatment with vehicle, sense oligonucleotides (SOs) and other AOs (sequences 1, 2 and 3) caused an increased DOM-induced HTR as well as a spontaneous HTR. The latter was abolished by treatment with the 5-HT2 receptor antagonist, ritanserin. Systematic investigation of the surgical and infusion procedures revealed that the enhanced HTR already appeared following drilling of the skull. This wounding can probably damage the blood-brain barrier and cause a stress-induced increase in serotonergic transmission. AO (sequence 4) treatment also abolished the spontaneous HTR. AO (sequence 4) treatment allowed the identification of specific central 5-HT2A receptor-mediated behaviours in the complex serotonergic syndrome induced by tryptamine in rats. Only bilateral convulsions and body tremors were significantly inhibited. The backward locomotion, hunched back and Straub tail were not affected, nor was cyanosis, an index of vasoconstriction induced by peripheral 5-HT2A receptor activation. Labelling of central 5-HT2C receptors by [3H]mesulergine, and 5-HT2C receptor-mediated anxiety were not attenuated by AO or SO treatment. Rats treated with AO (sequence 4) showed increased locomotor activity and a strong reactivity towards touching. We hypothesize that the down-regulation of functional 5-HT2A receptors may shift the balance between various 5-HT receptor subtypes. Our analysis of the behavioural consequences of AO treatment and the use of different AOs and SOs has shown that specific receptor-mediated behaviour can be identified.

Animals↗
PubMed1979

Central antiserotonin action of amitriptyline.

Amitriptyline (AMI) was studied in rats snd mice in order to find out whether it had a central antiserotonin activity, previously demonstrated for doxepin - a compound chemically related to AMI. It was observed that AMI at low doses antagonized the head twitch response to L-5-hydroxytryptophan or 5-methoxytryptamine, as well as tryptamine-induced convulsions. In the hind limb flexor reflex preparation of the spinal rat AMI acted as a serotonin antagonist: when administered alone, it did not change the flexor reflex but prevented its stimulation induced by serotoninmimetics (LSD, quipazine, fenfluramine) not affecting that one evoked by noradrenalinemimetics (clinidine). At higher doses, AMI revealed a noradrenolytic activity. The results indicate that AMI, similarly as doxepin, has a central antiserotonin activity.

5-Hydroxytryptophan↗
PubMed2000

Evaluation of a ginkgo biloba extract (EGb 761) in functional tests for monoamine oxidase inhibition.

A standardized extract of ginkgo biloba (EGb 761) was evaluated in functional tests for monoamine oxidase (MAO) inhibition in mice: l-dihydroxyphenylalanine (CAS 59-92-7,1-DOPA) potentiation, tryptamine (CAS 61-54-1) potentiation, 5-hydroxytryptophan (CAS 4350-07-6,5-HTP) potentiation and phenylethylamine (CAS 64-04-0) potentiation. The doses investigated (25, 50 and 100 mg/kg p.o once daily for 5 days) were those known to possess anti-stress properties in other animal models. In contrast to the reference substances investigated (nialamide (CAS 51-12-7), clorgyline (CAS 17780-75-5) and 1-deprenyl (CAS 14611-52-01), EGb 761 did not exhibit any activity indicative of MAO inhibition. It was concluded that MAO inhibition was not the mechanism primarily responsible for EGb 761's anti-stress activity.

5-Hydroxytryptophan↗
PubMed1982

Central action of amitriptyline N-oxide.

The central action of amitriptyline N-oxide (AMINO) has been compared with amitriptyline (AMI) in biochemical and pharmacological studies in rats and mice. It has been found in rats that both drugs prevent 6-OH-dopamine-induced depletion of brain noradrenaline (NA). At the same time AMINO increases and AMI lowers the NA level, both being without effect on 3-methoxy-4-hydroxyphenylglycol concentrations in the brain. AMINO and AMI potentiate the depletion of 5-hydroxytryptamine (5-HT) induced by p-chloroamphetamine in the rat brain and it may be considered as evidence that both drugs do not inhibit 5-HT uptake in vivo. Neither AMINO nor AMI affects the rat brain level of 5-HT but at higher doses they elevate the 5-hydroxy-indoleacetic acid concentrations. AMINO antagonizes the head twitch reaction induced by 5-hydroxytryptophan in mice and tryptamine convulsions in rats. The hyperthermia induced by fenfluramine (in rats at a high ambient temperature) as well as the stimulation of the hind limb flexor reflex in spinal rats, induced by fenfluramine or LSD, are also inhibited. AMINO antagonizes the 5-HT-induced increase in blood pressure in pithed rats. All the above effects are similar to those induced by AMI, only the active doses of AMINO are higher. The results presented indicate that AMINO, like AMI, inhibits NA uptake and is a 5-HT antagonist.

5-Hydroxytryptophan↗
PubMed1969

On the conformations of hallucinogenic molecules and their correlation.

There are only a few possible conformations of D-lysergic acid diethylamide and hallucinogenic derivatives of tryptamine and phenylethylamine. Of these possible conformations there is a high structural correlation among the probable conformations of active hallucinogenic molecules and between these conformations and the known conformations of several central nervous system transmitter molecules.

Chemistry, Pharmaceutical↗
PubMed2000

Synthesis and analgesic activity of N,N'-dicarbonyltryptamines.

5-Methoxytryptamine and L-tryptophan methyl ester were acylated with malonic acid, dimethyl malonate, or succinic anhydride to produce the corresponding N,N'-dicarbonyltryptamine derivatives. The analgesic activity was evaluated by the tail flick test. All of the compounds exhibited desirable analgesic potency. This result is consistent with that of N-(N-acetyl-L-tryptophanyl)-5-methoxytryptamine and confirmed that introducing substituted tryptamine into the amide chain of melatonin does enhance analgesic potency.

5-Methoxytryptamine↗
PubMed1996

Development of a novel derivatization reagent for the sampling and analysis of total isocyanate group in air and comparison of its performance with that of several established reagents.

Analytical reference standards generally are not available for non-monomeric isocyanate species, making accurate identification and quantitation by high-performance liquid chromatography (HPLC) difficult. A successful derivatizing reagent must react rapidly with all isocyanate groups, the derivatized isocyanate must be detectable selectively and at very low levels, and the detector used for quantitation must give a response proportional to the number of derivatized isocyanate groups present. A novel derivatizing reagent, 1-(9-anthracenylmethyl)piperazine (MAP), was prepared in an attempt to achieve these goals. Derivatives were prepared by reacting five mono- and difunctional isocyanates with MAP and three other established isocyanate derivatizing reagents. These reagents included 1-(2-methoxyphenyl)piperazine (MOPP),9-(methylaminomethyl)anthracene (MAMA), and tryptamine (TRYP). The relative reactivities of MAP, MOPP, TRYP, and MAMA with phenyl isocyanate were found to be 100, 88, 30, and 25, respectively. Average molar absorptivities at the absorbance maxima +/- compound-to-compound variabilities were, for MAP: 1.47 x 10(5) +/- 3.50%; MAMA: 1.38 x 10(5) +/- 7.07%: and TRYP: 3.98 x 10(4) +/- 13.1%. Average fluorescence responses were, for MAP: 100 +/- 32.6%; MAMA: 41.0 +/- 58.8%; and TRYP: 2.27 +/- 15.6%. A comparison of MAP and MOPP ureas by HPLC/ultraviolet (UV)/electrochemical (EC) gave average responses for UV, EC, and EC/UV for MAP: 117 +/- 7.3%, 52.1 +/- 6.6%, and 0.447 +/- 10.7%, respectively; for MOPP: 24.3 +/- 62.5%, 76.7 +/- 28.5%, and 4.28 +/- 59.1%, respectively. The favorable performance of MAP warrants its further study as a reagent for the determination of total isocyanate group in air.

Air Pollutants, Occupational↗
PubMed1979

Specificity of serotoninergic inhibition in Limulus lateral eye.

The receptor specificity for synaptically mediated lateral inhibition in Limulus lateral eye retina was studied by structure-activity correlations of the action of the putative indoleaminergic neurotransmitter, serotonin (5-HT), and its isomers and structural analogs, tryptamine (TRYP), 6-hydroxytryptamine (6HT), 5,6-dihydroxytryptamine (5,6-DHT), 5-hydroxydimethyltryptamine (5-HDMT), and 5-hydroxytryptophan (5-HTP). The 5-HT blockers, lysergic acid diethylamide (LSD), bromo-LSD (BOL), and cinanserin, were also tested. The inhibitory action of the indoleaminergic agonists is highly structure-specific. An hydroxyl group in the 5 position of the indole nucleus, sterically unencumbered by hydroxyls in neighboing positions, is essential. In order of decreasing potency, 5-HT, 5-HDMT, and 5-HTP are active agonists; TRYP, 6-HT, and 5,6-DHT are inactive. Configuration and mobility of the side chains of the active agonists also affect the interaction, and these side-chain characteristics correlate with agonist potency. The receptors for inhibitory action and for transmembranal transport in reuptake are different. Both active agonists and inactive analogs appear to be taken up (Adolph and Ehinger, 1975. Cell Tissue Res. 163:1-14). LSD and BOL have bimodal actions: direct inhibition and agonist blockade. These actions may be mediated via low-specificity presynaptic uptake receptor sites rather than highly specific, postsynaptic, agonist receptor sites.

5-Hydroxytryptophan↗
PubMedDate not supplied

Influence of biological matrix on chromatographic behavior and detection of selected acidic, neutral, and basic drugs examined by means of a standardized HPLC-DAD system.

Human serum, autopsy blood, and liver samples were extracted by means of liquid-liquid extraction at acidic and at basic pH and at basic pH following acid hydrolysis. Six selected basic and six selected acidic or neutral drugs were added to the extracts. The spiked and blank samples were examined by means of reversed-phase high-performance liquid chromatography (HPLC) under standardized conditions using diode array detection. The retention index (RI) values of drugs were determined using a 1-nitroalkane scale and secondary standards. The RI values were virtually unaffected by biological matrix. On the other hand, the detection of some substances may be impaired by matrix peaks occurring regularly in biological extracts. The retention index values and UV spectra of three identified (phenethylamine, tryptamine, and indole) and nine unidentified substances were included in an HPLC database.

Autopsy↗
PubMed2003

Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase.

The objective of this investigation was to screen for potential endogenous substrates for CYP2D6. Using recombinant CYP2D6, together with hepatic microsomes from CYP2D6-transgenic mice, human liver microsomes, and a specific anti-CYP2D6 monoclonal antibody, it was ascertained that CYP2D6 does not significantly metabolize the endogenous phenylethylamines 2-phenylethylamine, octopamine, synephrine, 3-methoxy-p-tyramine, 4-methoxy-m-tyramine, metanephrine, and normetanephrine, nor the indolethylamines tryptamine, serotonin, 6-methoxytryptamine, and melatonin, nor the beta-carbolines harman, norharman and tryptoline. However, the indolethylamines 5-methoxy-N,N-dimethyltryptamine (5-MDMT) and pinoline (6-methoxy-1,2,3,4-tetrahydro-beta-carboline) showed relatively high affinity for CYP2D6 in a spectral binding assay (K(s) 28 +/- 5, and 0.5 +/- 0.3 microm (mean +/- SEM), respectively) and were O-demethylated only by CYP2D6 in a panel of 15 recombinant common human P450s. Pinoline and 5-MDMT O-demethylase activities were 35- and 11-fold greater in liver microsomes from CYP2D6-humanized mice, respectively, than those in liver microsomes from control mice. Moreover, the increased activities were completely inhibited by an anti-CYP2D6 monoclonal antibody. Kinetic analysis with recombinant CYP2D6 gave K(m) and k(cat) values for 5-MDMT and pinoline O-demethylations of 12 +/- 1 microm and 65 +/- 1 min(-1) and 1.8 +/- 0.3 microm and 26 +/- 1 min(-1), respectively. These two substrates can be added to 5-methoxytryptamine, which we have recently reported to be an endogenous CYP2D6 substrate. CYP2D6 is therefore a relatively highly specific, high-affinity, high-capacity 5-methoxyindolethylamine O-demethylase. Polymorphic cytochrome CYP2D6 may therefore exert an influence on mood and behavior by the O-demethylation of these 5-methoxyindolethylamines found in the brain and pineal gland. These processes may also impact on mental and neurological health. The findings may open new vistas for the determination of CYP2D6 phenotype.

Animals↗
PubMed2006

The structure of Rauvolfia serpentina strictosidine synthase is a novel six-bladed beta-propeller fold in plant proteins.

The enzyme strictosidine synthase (STR1) from the Indian medicinal plant Rauvolfia serpentina is of primary importance for the biosynthetic pathway of the indole alkaloid ajmaline. Moreover, STR1 initiates all biosynthetic pathways leading to the entire monoterpenoid indole alkaloid family representing an enormous structural variety of approximately 2000 compounds in higher plants. The crystal structures of STR1 in complex with its natural substrates tryptamine and secologanin provide structural understanding of the observed substrate preference and identify residues lining the active site surface that contact the substrates. STR1 catalyzes a Pictet-Spengler-type reaction and represents a novel six-bladed beta-propeller fold in plant proteins. Structure-based sequence alignment revealed a common repetitive sequence motif (three hydrophobic residues are followed by a small residue and a hydrophilic residue), indicating a possible evolutionary relationship between STR1 and several sequence-unrelated six-bladed beta-propeller structures. Structural analysis and site-directed mutagenesis experiments demonstrate the essential role of Glu-309 in catalysis. The data will aid in deciphering the details of the reaction mechanism of STR1 as well as other members of this enzyme family.

Amino Acid Sequence↗
PubMed2005

Localization of tabersonine 16-hydroxylase and 16-OH tabersonine-16-O-methyltransferase to leaf epidermal cells defines them as a major site of precursor biosynthesis in the vindoline pathway in Catharanthus roseus.

The Madagascar periwinkle (Catharanthus roseus) produces the well known and remarkably complex anticancer dimeric alkaloids vinblastine and vincristine, which are derived by the coupling of vindoline and catharanthine monomers. Recent data from in situ RNA hybridization and immunolocalization suggest that combinatorial cell factories within the leaf are involved in vindoline biosynthesis. In this study, the cell types responsible for vindoline biosynthesis were identified by laser-capture microdissection/RNA isolation/RT-PCR to show that geraniol hydroxylase, secologanin synthase, tryptophan decarboxylase, strictosidine synthase, strictosidine ss-glucosidase and tabersonine 16-hydroxylase can be detected preferentially in epidermal cells. A new and complementary application of the carborundum abrasion (CA) technique was developed to obtain epidermis-enriched leaf extracts that can be used to measure alkaloid metabolite levels, enzyme activities and gene expression. The CA technique showed that tabersonine and 16-methoxytabersonine, together with 16-hydroxytabersonine-16-O-methyltransferase, are found predominantly in Catharanthus leaf epidermis, in contrast to vindoline, catharanthine and later enzymatic steps in vindoline biosynthesis. The results show that leaf epidermal cells are biosynthetically competent to produce tryptamine and secologanin precursors that are converted via many enzymatic transformations to make 16-methoxytabersonine. This alkaloid or its 2,3 dihydro-derivative is then transported to cells (mesophyll/idioblast/laticifer) within Catharanthus leaves to complete the last three or four enzymatic transformations to make vindoline.

Base Sequence↗
PubMed1976

Monoamine oxidase activity in the fetal lung and liver.

Monoamine oxidase (MAO) in lung and liver is important in the degradation of circulating 5-hydroxytryptamine. These sites of MAO activity have been investigated histochemically in the human fetus of 12 to 18 weeks gestation. Enzyme activity could be demonstrated in the liver by both tryptamine and adrenaline oxidation. In the lung, MAO activity was present only when adrenaline was used to substrate. It may be, therefore, that in the premature baby the capacity of MAO to metabolize 5-hydroxytryptamine is not fully developed, which could lead to deleterious effects on pulmonary function.

Epinephrine↗
PubMed1981

Characterisation of inhibitory 5-hydroxytryptamine receptors that modulate dopamine release in the striatum.

The effect of a series of indoleamines on the potassium-evoked tritium release of previously accumulated [3H]dopamine from rat striatal slices has been investigated. The indoleamines 5-hydroxytryptamine, 5-methoxytryptamine, 5-methoxy-N,N'-dimethyltryptamine and tryptamine (10(-7) to 10(-5) M) all reduced potassium-evoked release of tritium, to a maximum of 50%. The uptake of [3H]dopamine was unaffected by these compounds. A series of 5-hydroxytryptamine antagonists were examined for their ability to reduce the inhibition of potassium-evoked tritium release induced by 5-methoxytryptamine. The relative order of antagonist potency obtained was methysergide greater than metergoline greater than methiothepin greater than cinanserin greater than cyproheptadine greater than mianserin, and was consistent with an action on 5-hydroxytryptamine receptors. It is concluded that there are inhibitory 5-hydroxytryptamine receptors located on the terminals of dopaminergic neurones in the striatum.

Animals↗
PubMed1982

5-hydroxytryptamine stimulates [3H]dopamine release from the fish retina.

Serotonin (5-hydroxytryptamine, 5-HT; 0.5 micro M and above) stimulated the release of [3H]dopamine ([3H]DA) from particulate fractions of the carp (Cyprinus carpio) retina. The 5-HT effect was dose- and Ca2+-dependent, and was structurally specific. A similar response was not elicited by the other indoles (5,6-dihydroxytryptamine, 5,7-dihydroxytryptamine, 5-hydroxytryptophan, or 5-hydroxyindoleacetic acid) examined. An increase in [3H]DA release was elicited by addition of 5-HT agonists (5-methoxytryptamine, 5-methoxy-N,N-dimethyltryptamine, and tryptamine), but not antagonized by three 5-HT antagonists (metergolin, methysergide, and spiperone). Either DA alone or noradrenaline (0.5 mM) produced a large increase in [3H]DA release from the particulate fractions, but this action was Ca2+-independent. Further, no significant release of [3H] gamma-aminobutyric acid could be evoked by 5-HT (0.5 mM) under similar experimental conditions. Taken together, the present data suggest that 5-HT stimulates [3H]DA release from the fish retina through a specific receptor-mediated mechanism on dopaminergic terminals, but not through an exchange or nonspecific phenomenon.

5-Methoxytryptamine↗