Adrenaline oxidase

This group of enzymes catalyzes the oxidation of amines. Amine oxidase [EC 1.4.3.4], a flavin-containing enzyme (also known as monoamine oxidase, tyramine oxidase, tyraminase, or adrenalin oxidase) catalyzes the reaction of an organic amine R—CH2—NH2) with dioxygen... 

The role of amine oxidase in the inactivation of sympathomimetic amines rests on a much firmer basis. The enzymatic oxidative deamination of tyramine was described first by Hare (87). Kohn (105) partially purified it but the enzyme is widely distributed in mammalian tissues (30,109), is cyanide insensitive (15), and has resisted isolation. The name monamine oxidase has been suggested for the enzyme (154) referred to in the literature as tyramine oxidase, adrenaline oxidase (40), and aliphatic amine oxidase (128). 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Adrenaline Adrenal medulla Fe and Cu oxidases Cu oxidases in degradation... 

Tyramine is an amino acid which is present in large quantities in protein rich, fermented and stored products like some cheeses, sausages, red wines, beers etcetera. Tyramine is metabolized into nor-adrenaline by the enzyme mono-amino-oxidase (MAO). If MAO is inhibited by drags nor-adrenaline is accumulated and can give hypertensive crises. 

Urine catecholamines may also serve as biomarkers of disulfoton exposure. No human data are available to support this, but limited animal data provide some evidence of this. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in female rats, respectively, within 72 hours of exposure (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). Because organophosphates other than disulfoton can cause an accumulation of acetylcholine at nerve synapses, these chemical compounds may also cause a release of catecholamines from the adrenals and the nervous system. In addition, increased blood and urine catecholamines can be associated with overstimulation of the adrenal medulla and/or the sympathetic neurons by excitement/stress or sympathomimetic drugs, and other chemical compounds such as reserpine, carbon tetrachloride, carbon disulfide, DDT, and monoamine oxidase inhibitors (MAO) inhibitors (Brzezinski 1969). For these reasons, a change in catecholamine levels is not a specific indicator of disulfoton exposure. 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

Lorazepam is a short-acting benzodiazepine indicated for use in relieving anxiety and insomnia. Lorazepam may also be administered perioperatively to alleviate pain and in status epilepticus. Imipramine is a tricyclic antidepressant, paroxetine is a selective serotonin re-uptake inhibitor, venlafaxine is a serotonin and adrenaline re-uptake inhibitor and moclobemide is a reversible monoamine oxidase inhibitor. Imipramine, paroxetine, venlafaxine and moclobemide are all classified as antidepressants. 

The first drug-drug interaction alert issued by the Committee in 1966 concerned the risks from interactions between preparations containing adrenaline or noradrenaline and monoamine oxidase (MAO) inhibitors used for the treatment of depression. 

Adrenaline is synthesised in the adrenal medulla and at sympathetic nerve endings from phenylalanine and metabolised by oxidation (monoamine oxidase MAO) or conjugation (catechol 0-methyl transferase COMT). It is excreted in the urine as vanillylmandelic acid. Its main physiological effects are at pi and a adrenoceptors, with less marked effects at (P2... 

Newer MAOI drugs are selective for the MAO-A subtype of the enzyme, and are less likely to interact with foods or other drugs. Monoamine oxidase (MAO) inactivates monoamine substances, many of which are, or are related to, neurotransmitters. The central nervous system mainly contains MAO-A, whose substrates are adrenaline (epinephrine), noradrenaline (norepinephrine), metanephrine, and 5-hydroxyti7ptamine (5-HT), whereas extra-neuronal tissues, such as the liver, lung, and kidney, contain mainly MAO-B which metabolises p-phenylethylamine, phenylethanolamine, o-tyramine, and benzylamine. 

These reactions, which have provided a means of inhibiting the flavin-linked monoamine oxidases, enable us to end on a clinical note. The monoamine oxidases are responsible for the deamination of monoamines such as adrenaline, noradrenaline, dopamine, and serotonin, which act as neurotransmitters. Imbalances in the levels of monoamines cause various psychiatric and neurological disorders Parkinson s disease is associated with lowered levels of dopamine, and low levels of other monoamines are associated with depression. Inhibitors of monoamine oxidases may consequently be used to treat Parkinson s disease and depression. The flavin moiety is covalently bound to the enzyme by the thiol group of a cysteine residue (equation 9.17). The acetylenic suicide inhibitor N,N-dimethyl-propargylamine inactivates monoamine oxidases by alkylating the flavin on N-5.25 A likely mechanism for the reaction is the Michael addition of the N-5 of the reduced flavin to the acetylenic carbon 2... 

Principally because amine oxidase was so abundantly present in the body and could be shown to deaminate certain pressor amines in vitro, it has been thought by some to play a role in the in vivo inactivation of adrenaline and in the etiology of hypertension. The administration of crude amine oxidase has been reported to have decreased the blood pressure of normal and hypertensive rats (143), but this has not provoked substantiation. Croxatto and Croxatto (53, 54) have shown that renal hypertensinase and amine oxidase were different enzymes. Also, Bing, Zucker, and Perkins (34) found angiotonin and amine oxidase to be fundamentally different. Thus the hypertensin and the phenylethyl (pressor) amine approaches to hypertension seem quite dissimilar on these grounds. 

As stated by Beyer, it now does appear that both noradrenaline and adrenaline are implicated in the humoral mediation of adrenergic nerve impulses. The hypothesis that adrenoxine as produced by any action of a catechol oxidase in the body acts under appropriate conditions as the vasodilator substance presently appears to be very doubtful, although some of the evidence along this line presented by Bacq (1) and by Heirman and Bacq (7) appeared to be reliable. Shortly after their reports appeared Carroll Handley and the author in the pharmacology laboratory of the University of California Medical School tried to confirm the apparent reversal of net vasomotor effects of catechol oxidase oxidation of adrenaline solutions but failed to observe any effects beyond those that could be ascribed to the destruction of a part of the adrenaline activity. 

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). 

A phenol oxidase from the fish cestode, Penetrocephalus ganapatii, has been characterised bio-chemically and has been shown to have a pH optimum of 7.4 (Fig. 7.9) (362). Its activity with three different substrates, dopamine, adrenaline (= epinephrine) and dopa are shown in Table 7.4 and Fig. 7.10 the action of various inhibitors is shown in Table 7.5. The Michaelis constant for dopamine was 189 p.M and the enzyme was stable between 20 and 40°C. The action of various inhibitors was also studied. 

Dopa and dopamine are important compounds because they are the precursors oxidase (Chapter 50) hydroxyiates stereospecifically at the benzyiic position to to adrenaline in humans. Decarboxylation of dopa gives dopamine, which an give noradrenaline (norepinephrine). 

Monoamine oxidase inhibitors (MAOIs), which were amongst the first antidepressant drugs to be used clinically. They affect one or both of the brain monoamine oxidase enzymes that play a role in the metabolism of serotonin, noradrenaline, dopamine and adrenaline. MAOIs inhibit breakdown of the neurotransmitters important in determining mood, which results in the antidepressant effect. 

Catecholamines (adrenaline, noradrenaline, dopamine, dobutamine, isoprenaline) (plasma approx. 2 min) are metabolised by two enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). These enzymes are present in large amounts in the liver and kidney and account for most of the metabolism of injected catecholamines. MAO is also present in the intestinal mucosa (and in nerve endings, peripheral and central). Because of these enzymes catecholamines are ineffective when swallowed, but noncatecholamines, e.g. salbutamol, amphetamine, are effective orally. 

Monoamine oxidase inhibitors have been said to potentiate the hypertensive effects of adrenaline, bnt there is no good clinical evidence of such an interaction (21). Nevertheless, care should be taken when contemplating the use of adrenaline in patients taking a monoamine oxidase inhibitor. 

Superoxide can also be produced by other enzymes, such as the range of flavin oxidases located in peroxisomes, and by oxidation of certain compounds including ascorbic acid, thiols, and adrenaline in the presence of transition metal ions. The autoxidation of reduced transition metal can also generate the superoxide... 

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