Monoamine oxidase catecholamine metabolization

The antidepressants, generally, produce their therapeutic effects by blocking the reuptake of one or more catecholamines (norepinephrine, serotonin, and dopamine), which leads to a decrease (down-regulation) of the number of post-synaptic receptors—generally within seven to twenty-one days, coinciding with the onset of clinical effect (see chapter 3). The MAOIs block monoamine oxidase, which metabolizes the catecholamines stored at the nerve ending of the presynaptic neuron—thereby making more catecholamine available. Stimulants increase the release of catecholamines. Buspirone is a 5-HT lA receptor blocker. 

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

Ordinarily, low concentrations of catecholamines are free in the cytosol, where they may be metabolized by enzymes including monoamine oxidase (MAO). Thus, conversion of tyrosine to l-DOPA and l-DOPA to dopamine occurs in the cytosol dopamine then is taken up into the storage vesicles. In norepinephrine-containing neurons, the final P-hydroxylation occurs within the vesicles. In the adrenal gland, norepinephrine is N-methylated by PNMT in the cytoplasm. Epinephrine is then transported back into chromaffin granules for storage. 

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. 

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+Oj B tyrosine hydroxylase+ tetrahydropteridme+Fe+ +Oj C=dopa decarboxylase+pyridoxal phosphate D= dopamine beta-oxidase+ascorbate phosphate+Cu+ +Oj E=phenylethanolamine N-methyltransferase+S-adenosylmethionine l=monoamine oxidase and aldehyde dehydrogenase 2=catechol-0-methyltransferase+S-adenosylmethionine.

Two enzymes are concerned in the metabolism of catecholamines, namely monoamine oxidase, which occurs mainly intraneuronally, and catechol-O-methyltransferase, which is restricted to the synaptic cleft. The importance of the two major forms of monoamine oxidase, A and B, will be considered elsewhere. 

Monoamine oxidase (MAO) inhibitors MAO and COMT are the 2 major enzyme systems involved in the metabolism of catecholamines. Do not treat patients concomitantly with entacapone and a nonselective MAO inhibitor. 

The metabolism of catecholamines is much slower and more complex than that of ACh. The degradative pathways are shown in figure 4.7. The principal, although nonspecific, enzyme in the degradation is monoamine oxidase (MAO), which dehydrogenates... 

Dopamine metabolism inhibitors interfere with monoamine oxidase and catecholamine-0-methyltransferase. Monoamine oxidase will be discussed separately in chapter 8. 

Norepinephrine and epinephrine can be metabolized by several enzymes, as shown in Figure 6-6. Because of the high activity of monoamine oxidase in the mitochondria of the nerve terminal, there is significant turnover of norepinephrine even in the resting terminal. Since the metabolic products are excreted in the urine, an estimate of catecholamine turnover can be obtained from laboratory analysis of total metabolites (sometimes... 

Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). 

Dopamine, norepinephrine and epinephrine are products of the metabolism of dietary phenylalanine. This is an interesting sequence of reactions in that we will be discussing not only the three neurotransmitters formed but also considering the DOPA precursor and its use in the treatment of Parkinson s Disease. These molecules are also called catecholamines. Catechol is an ortho dihydroxyphenyl derivative. Degradation of the final product in the pathway, epinephrine, can be accomplished by oxidation (monoamine oxidase - MAO)or methylation (catecholamine 0-methyl transferase - COMT). The diagram on the next page illustrates the scheme of successive oxidations which produce the various catecholamines. 

Degradation of catecholamines The catecholamines are inacti vated by oxidative deamination catalyzed by monoamine oxidase (MAO), and by O-methylation carried out by catechol-O-methyl-transferase (COMT, Figure 21.15). The two reactions can occur in either order. The aldehyde products of the MAO reaction are axi dized to the corresponding acids. The metabolic products of these reactions are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine. 

Catecholamine neurotransmitters are subsequently inactivated by enzymic methylation of the 3-hydroxyl (via catechol-O-methyltransferase) or by oxidative removal of the amine group via monoamine oxidase. Monoamine oxidase inhibitors are sometimes used to treat depression, and these drugs cause an accumulation of amine neurotransmitters. Under such drug treatment, simple amines such as tyramine in cheese, beans, fish, and yeast extracts are also not metabolized and can cause dangerous potentiation of neurotransmitter activity. 

In sympathetic nerve terminals, as well as the brain, the adrenal medulla, and sympathetic postganglionic terminals, there are osmophilic granules (synaptic vesicles) that are capable of storing high concentrations of catecholamine (a complex with adenosine triphosphate, or ATP, and protein). The stored amines are not metabolized by the intersynaptosomal mitochondrial enzyme (monoamine oxidase). 

There are two enzymes capable of metabolizing catecholamines. The first is monoamine oxidase (MAO), a mitochondrial enzyme that oxidatively deaminates catecholamines, tyramine, serotonin, and histamine. MAO is further subclassified as either monoamine oxidase A, which metabolizes norepinephrine and is inhibited by tranylcypromine, and monoamine oxidase B, which metabolizes dopamine and is inhibited by 1-deprenyl. Catechol-O-methyltransferase (COMT), a soluble enzyme present mainly in the liver and kidney, is also found in postsynaptic neuronal elements. About 15% of norepinephrine is metabolized postsynaptically by COMT. 

Figure 16.10 Catecholamine biosynthesis and metabolism. MAO, monoamine oxidase COMT, catecholamine-O-methyltransferase SAM, 5-adenosylmethionine.

Monoamine oxidases catalyze oxidative deamination of many primary, secondary, and tertiary amines. They have a wide tissue distribution including brain, liver, and intestine. A variety of endogenous amines, such as catecholamines, and pharmacological substances are metabolized. The products of primary amines are the corresponding aldehydes, ammonia, and hydrogen peroxide. 

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. 

NE is synthesized by tyrosine hydroxylation (meta ring position) followed by decarboxylation and side chain p carbon hydroxylation. The synthesis of this catecholamine is regulated by tyrosine hydroxylase. Tyrosine hydroxylation is also a key step in the synthesis of two other important catecholamines, dopamine and epinephrine. NE is packaged via active transport into synaptic (or chromaffin) vesicles prior to release by neuronal depolarization. The effects of NE are mediated by adrenergic receptors (a or P) which are G protein coupled resulting in either increases or decreases in smooth muscle tone as well as increases in cardiac rate and contractility. These effects arise out of receptor mediated increases in intracellular Ca and activation or inhibition of various protein kinases. The effects of NE are terminated essentially as a result of its active transport into the presynaptic nerve ending via an energy and Na" dependent process which utilizes the norepinephrine transporter (NET). Ultimately, NE and other catecholamines are metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). 

Wliile the cyclics block the uptake of amines, MAOls prc cnt the breakdown of the neurotransmitters (Cohen, 1997 Cooperrider, 1988 Meyer Quenzer, 2005). The enzyme monoamine oxidase metabolizes a variety of neurotransmitters, including norepinephrine and serotonin. MAOls inhibit this degradation process and thus enhance the availability of the transmitter within the neuron. Thii.s, the actions of the cyclics and MAOls each arc consistent u ith the hypothesis that decreased brain catecholamine activity causes depression and that these antidepressants (using different mechanisms) reverse this process by increasing catecholamine activity in the brain. 

Epinephrine is well absorbed after oral administration but is rapidly inactivated in the gut mucosa. When intravenously injected or infused, the onset of drug effect is rapid (within 5 min for dopamine and 3-10 min for epinephrine) and the duration of drug effect is short (10 min for dopamine, 1 or 2 min for norepinephrine, and 15 min to hours for epinephrine depending on route of administration). Exogenous catecholamine in the circulation is rapidly and efficiently taken up by adrenergic neurons. Catecholamine is metabolized by monoamine oxidase, which is localized largely in the outer membrane of neuronal mitochondria, and by catechol-0-methyl transferase, which is found in the cytoplasm of most animal tissues, particularly the kidneys and the liver. 

Central Nervous System. Dopamine monooxygenase (DMO) is an enzyme that requires copper, as a cofactor and uses ascorbate as an electron donor. This enzyme catalyzes the conversion of dopamine to norepinephrine, the important neurotransmitter. There are soluble and membrane-bound forms of the enzyme, the latter being found in the chromaffin granules of the adrenal cortex. Monoamine oxidase, one of the numerous amine oxidases, is a copper-containing enzyme that catalyzes the degradation of serotonin in the brain and is also involved in the metabolism of the catecholamines. 

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