5-Hydroxytryptamine oxidase

Warenycia MW, Smith KA, Blashko CS, et al. 1989c. Monoamine oxidase inhibition as a sequel of hydrogen sulfide intoxication Increases in brain catecholamine and 5-hydroxytryptamine levels. Arch Toxicol 63 131-136. 

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

This condition is cansed by a deficiency of one or more of the monoamine nenrotransmitters in the brain (e.g. noradrenaline, dopamine, 5-hydroxytryptamine). One means of increasing the concentration of the neurotransmitters is to inhibit one of the enzymes that degrade the neurotransmitter in the brain. For the monoamines, a key degradative enzyme is monoamine oxidase, which catalyses the reaction... 

Figure 2.18. The major pathway leading to the synthesis and metabolism of 5-hydroxytryptamine (5-HT). Metabolism of tryptophan to tryptamine is a minor pathway which may be of functional importance following administration of a monoamine oxidase (MAO) inhibitor. Tryptamine is a trace amine. L-Aromatic amino acid decarboxylase is also known to decarboxylate dopa and therefore the term "L-aromatic amino acid decarboxylase" refers to both "dopa decarboxylase"...

Grahame-Smith DG, Green AR The role of brain 5-hydroxytryptamine in the hyperactivity produced in rats by lithium and monoamine oxidase inhibition. Br J Pharmacol 52 19-26, 1974... 

Presynaptic receptor that is activated by a neurotransmitter from an adjacent neuron the type of neurotransmitter activating the heteroceptor differs from that released from the axon. 5-Hydroxyindoleacetic acid, the main metabolite of 5-hydroxytryptamine (serotonin) formed by monoamine oxidase. 

Celada P, Artigas F. Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat. Nanny n-Schrnicdcbcrgs Arch Pharmacol 1993 347 583-590. 

The excretion of amines is unusual in animals. Amines are highly toxic and one method employed by vertebrates to detoxify them is via monoamine oxidase, an enzyme which has been detected in H. diminuta (569). Amines can arise from the decarboxylation of the appropriate amino acid, e.g. glycine and alanine can give rise to methylamine and ethylamine, respectively. Another possible source of amines may be the reduction of azo or nitro compounds (39) and azo- and nitro-reductase activity has been reported from M. expansa (180, 181). Furthermore, the physiologically active amines octopamine, dopamine, adrenalin and serotonin (5-hydroxytryptamine) have been demonstrated in cestodes (283, 296, 435, 681, 682, 758, 859), where they probably function predominantly as neurotransmitters (see Chapter 2). 

List of Abbreviations Ach, acetylcholine AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid CNS, central nervous system COMT, catechol-O-methyltransferase DA, dopamine DRP-2, dihy-dropyrimidinase-related protein 2 DSM, diagnostic and statistical manual of mental disorders GNAS1, guanine nucleotide-binding protein (G-protein) alpha stimulating activity polypeptide 1 5-HIAA, 5-hydroxyindole acetic acid 5-FIT, serotonin (5-hydroxytryptamine) MAO, monoamine oxidase MHPG, 3-methoxy-4-hydroxyphenylglycol NE, norepinephrine NMDA, N-methyl-D-aspartate PCP, phencyclidine SSRI, selective serotonin reuptake inhibitor SDS, schedule for the deficit syndrome... 

The HPLC method described here allows the assay of both isoforms in the same run by using 5-hydroxytryptamine and 3-methoxy-4-hydroxybenzyl-amine as highly selective substrates for the A and B isoforms, respectively. The product of 5-hydroxytryptamine that is quantitated is 5-hydroxyindole-2-carboxylic acid, which is obtained by including aldehyde dehydrogenase in the assay mixture to oxidize the intermediate aldehyde. The product of monoamine oxidase B is 3-methoxy-4-hydroxybenzaldehyde. The internal standards used are 5-hydroxyindole-2-carboxylic acid and 3,4-dihydroxyben-zoic acid. 

Indolealkylamines. GC-MS methods applied in studies of the biochemical pharmacology of indoleamines parallel work on the catecholamines. SIM assays for serotonin (5-hydroxytryptamine), 5-methoxytryptamine, JV-acetylserotonin and melatonin (5-methoxy-N-acetyltryptamine) in rat pineal and brain tissue have been described [453,469]. Pentafluoro-propionyl derivatives and structural homologue standardisation were employed with detection limits in the subpicomole range. Estimation of central indoleamine turnover in man currently depends upon metabolite determination in CSF. Ion monitoring determination of indole-3-acetic acid [454] a metabolite of tryptamine, and isotope dilution assays for 5-hydroxyindoleacetic acid (5-HIAA) [455,458] have been reported. Serotonin is converted by central monoamine oxidase to 5-HIAA and the measurement of this metabolite, formerly by fluorimetry, is of interest in patients with CNS disorders [470]. GC-MS has also contributed to the identification of N,N-dimethyltryptamine in vitro [471] and isotope dilution technique has been applied to the measurement of this metabolite in control subjects and in psychiatric patients [472]. 

MDMA (3.4-methylenedioxymethylamphetamjne EA 1475 XTC Ecstasy E ) has amphetamine-like actions, and induces release of, and is a (re-) uptake inhibitor of 5-hydroxytryptamine. Also, it is a monoamine-oxidase INHIBITOR (MAOI, type A), slowing catabolism of 5-HT. It is a PSYCHOTROPIC AGENT and drug of abuse. 

Most antidepressants in clinical use today act by enhancing the neurotransmission of serotonin [5-hydroxytryptamine (5-HT)], norepinephrine [NE noradrenaline (NA)], or both. They do so either by blocking the reuptake (transport) of neurotransmitter, blocking the metabolism of neurotransmitter [i.e., monoamine oxidase (MAO) inhibitors], or by direct action on a neurotransmitter receptor. Hence, the antidepressants can be classified on the basis of their putative mechanisms of action (Table 8.2 and Figs. 8.1-8.4). Agents that block neurotransmitter reuptake can be further divided into those that are non-selective (e.g., tricyclic antidepressants with mixed action), serotonin-selective reuptake... 

Aral, Y. Kim, S.Y. Kinemuchi, H. Tadano, T. Satoh, S. and Satoh, N. Inhibition of brain type A monoamine oxidase and 5-hydroxytryptamine uptake by two amphetamine metabolites, p-hydroxyamphetamine and p-hydroxynorephedrine. JNeurochem 55 403-408, 1990. 

CGRP calcitonin gene-related peptide GABA y-aminobutyric acid 5-HT serotonin, 5-hydroxytryptamine IHS International Headache Society MAOIs monoamine oxidase inhibitors NSAIDs nonsteroidal anti-inflammatory drugs SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressant... 

As well as the microsomal enzymes involved in the oxidation of amines, there are a number of other amine oxidase enzymes which have a different subcellular distribution. The most important are the monoamine oxidases and the diamine oxidases. The monoamine oxidases are located in the mitochondria within the cell and are found in the liver and also other organs such as the heart and central nervous system and in vascular tissue. They are a group of flavoprotein enzymes with overlapping substrate specificities. Although primarily of importance in the metabolism of endogenous compounds such as 5-hydroxytryptamine they may be involved in the metabolism of foreign compounds. The enzyme found in the liver will deaminate secondary and tertiary aliphatic amines as well as primary amines, although the latter are the preferred substrates... 

MAO catalyzes the oxidative deamination of catecholamines, 5-hydroxytryptamine (serotonin), and other monoamines, both primary such as NE, and secondary such as EP. It is one of several oxidase-type enzymes whose coenzyme is the flavin-adenine-dinucleotide (FAD) covalently bound as a prosthetic group (Fig. 9-3). The isoalloxazine ring system is viewed as the catalytically functional component of the enzyme. In a narrow view N-5 and C-4a is where the redox reaction takes place (i.e., +H+, +le or -H+, -le), although the whole chromophoric N-5-C-4a-C-4-N-3-C-2-N-l region undoubtedly participates. Figure 9-3 is a proposed structure of MAO isolated from pig brain (Salach et al., 1976).4... 

Spector and Willoughby - have pointed out that the vascular changes in the acute inflammatory reaction may be due to the destruction of local vasoconstrictor substances such as adrenaline. Evidence in favour of this mechanism includes the observation that increased capillary permeability after thermal injury is suppressed by iproniazid and other monoamine oxidase inhibitors. Such inhibitors are known to inhibit the conversion of adrenaline, noradrenaline, 5-hydroxytryptamine and other amines to inactive metabolites. The authors provide evidence that the action of the monoamine oxidase inhibitors on capillary permeability is dependent on their anti-enzymic activity and not on some other unrelated property. Nevertheless, the evidence remains indirect an attempt to detect pressor amines in the plasma of burned animals was unsuccessful. The potentiating effect of bretylium and the antagonistic action of an adrenolytic substance, dibenamine, on the action of iproniazid suggest that it is local depots of adrenaline rather than noradrenaline or 5-hydroxytryptamine which are involved. Independent support for this suggested role of catecholamines... 

The enzymes involved in the formation of the catecholamines are of low specificity. DOPA decarboxylase, or an enzyme closely akin to it, is concerned in the formation of 5-hydroxytryptamine > dopamine-/9-oxidase has been shown to be capable of hydroxylating the jd-carbon atom of a number of tyramine derivatives - and phenylethanolamine A-methyltransferase is equally unselective in its A-methylation of noradrenaline derivatives . This lack of specificity suggests the possibility that alternative pathways for the formation of noradrenaline and adrenaline might exist in vivo. Some of the putative intermediaries in these other pathways have been shown to occur naturally and one of them, octopamine (/) is found in the brain . 

A number of routes by which 5-hydroxytryptamine may be broken down or otherwise inactivated have been established . The most important involves monoamine oxidase, which converts 5-hydroxytryptamine into 5-hydroxyindoleacetaldehyde II). Catabolism is completed by an aldehyde dehydrogenase which forms 5-hydroxyindoleacetic acid III), the principal urinary metabolite of 5-hydroxytryptamine. Like noradrenaline, 5-hydroxy-tryptamine can also be conjugated with glucuronic and sulphuric acids. 

An explanation of the mode of action of the monoamine oxidase inhibitors in terms of their intervention in central transmission processes is difficult for several reasons. Monoamine oxidase is widely distributed in the body and some of the consequences of its inhibition may arise peripherally in the brain the enzyme participates in the inactivation of at least three substances (noradrenaline, dopamine and 5-hydroxytryptamine). Not all monoamine oxidase inhibitors have antidepressant activity but those that have may owe at least part of their activity to an action other than enzyme inhibition. 

Barlow, R.B. 1961. Effects of amine oxidase of substances which antagonize 5-hydroxytryptamine more than tryptamine on the rat fundus strip. British Journal of Pharmacology Vol. 16 153-162. 

Lessin, A.W. Long, R.F. Parkes, M.W. 1967. The central stimulant properties of some substituted indolealkylamines and 6-carbolines and their activities as inhibitors of monoamine oxidase and the uptake of 5-hydroxytryptamine. British Journal of Pharmacology and Chemotherapy Vol. 29 70-79. 

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