Metabolism of catecholamines

Some biologically important o-quinones can react with the superoxide ion giving catechol derivatives, which may play a role in many diseases. For example, compounds bearing a nitro-catechol moiety have been claimed to be efficient catechol-0-methyl transferase inhibitors (Suzuki et al. 1992, Perez et al. 1992). The transferase is the first enzyme in the metabolism of catecholamine a hyperactivity of this enzyme leads to Parkinson s disease. Therefore, prediction of biological activity and antioxidant properties of quinones is an important challenge for researchers. 

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... 

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

Factors that influence the disposition of catecholamines will affect the toxicity. For instance, compounds that inhibit the uptake of noradrenaline reduce the destruction of adrenergic nerve terminals but not of dopaminergic ones. Interference with the oxidative metabolism of catecholamines also influences the toxicity of 6-hydroxydopamine. 

The pharmacokinetics of morphine have been studied,201-203 as has its receptor binding,204-206 and its effects on hypothermia,207 on calcium uptake by synaptosomes208 and lysed synaptosomes,209 on metabolism of catecholamine in brain,210 on levels of corticosteroids and growth hormone in plasma,211 on leuteinising hormone,212 follicle-stimulating hormone,212 and prolactin,212-215 on neuroendocrine function,216 on brain function and biochemistry,217-226 on behaviour,227-240 on the gastrointestinal tract241 and on the cardiovascular... 

Despite the surge of genetic studies in schizophrenia, few have examined genes in relation to the deficit syndrome. One gene that has received some attention is the catechol-O-methyltransferase (COMT) gene. COMT is an enzyme involved in the metabolism of catecholamine neurotransmitters. In the general... 

In its acute stages, benzene toxicity appears to be due primarily to the direct effects of benzene on the central nervous system, whereas the peripheral nervous system appears to be the target following chronic low-level exposures. In addition, because benzene may induce an increase in brain catecholamines, it may also have a secondary effect on the immune system via the hypothalamus-pituitary-adrenal axis (Hsieh et al. 1988b). Increased metabolism of catecholamines can result in increased adrenal corticosteroid levels, which are immunosuppressive (Hsieh et al. 1988b). 

Dexamphetamine sulphate acts by stimulating the release of norepinephrine and dopamine from storage sites and may also slow down the metabolism of catecholamines by inhibiting MAO. Usually about 30% is excreted unchanged in the urine this urinary excretion reaches 60% when the urine is acidic (pH 5.5-6). It is metabolized by cytochrome P450. 

Axelrod J (1966) Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol Rev 18(1) 95-113 Backman L, Nyberg L, Lindenberger U, Shu-Chen Li, Farde L (2006) The correlative triad among aging, dopamine, and cognition current status and future prospects. Neurosci Biobehav Rev 30 791-807... 

The basis for the high diagnostic efficacy of plasma free metanephrines is explained by several factors (1) plasma free metanephrines are produced by metabolism of catecholamines within pheochromocytomas, a process that occurs continuously and independently of variations in catecholamine release by tumors (2) normally only small amounts of metanephrines are produced in the body, and these are relatively unresponsive to sympathoadrenal activation compared with the parent amines and (3) VMA and the metanephrines commonly measured in urine are different metabofites from the free metanephrines measured in plasma, and are produced in different parts of the body by metabolic processes not directly related to the tumor itself." ... 

Synthesis and metabolism of catecholamines. Arrows indicate molecular conversions catalyzed by specific enzymes. Bold arrows indicate major (preferred) pathways. Enzymes (I) tyrosine hydroxylase (2) aromatic L-amino acid decarboxylase (3) dopamine-jSymonooxygenase (4) PNMT (5) cateckel-o-methyltransferase (6) monoamine oxidase. 

Figure 7.1 Pathways of synthesis and metabolism of catecholamines with enzymes catalyzing various reactions. (1) Tyrosine hydroxylase (2) aromatic amino acid decarboxylase (3) phenylamine-P-hydroxylase (4) phenylethanolamine-A-methyltransferase (5) monoamine oxidase plus aldehyde dehydrogenase (6) catechol-O-methyltransferase (7) conjugating enzymes about 95% phenolsulfo-transferase and 5% phenolglucuronatetransferase (in human). DOPA, dihydroxyphenylalanine DOMA, dihydroxymandelic acid DHPG, dihydroxyphenylglycol DOPAC, dihydroxyphenylacetic acid HVA, homovanillic acid MHPG, methoxyhydroxylphenylglycol VMA, vanilmandelic acid...

The complexity and interrelationships of precursors, bioactive compounds, and their metabolized products can be appreciated by reviewing the biosynthesis and metabolism of catecholamines (Chapter 9). Figures 3-4 and 3-5 illustrate aspects of the metabolic profile of aspirin and chlorpromazine, respectively. The number of metabolites and conjugates possible for chlorpromazine could probably reach 100. Many of them have been identified in humans and experimental animals. 

It is now recognized that adenosine receptors are linked through appropriate guaiune nucleotide-binding regulatory proteins (G-proteins), not only to adenyl cyclase but also to other effector systems. Moreover, theophylline may inhibit the synthesis of prostaglandin and reduce the uptake or metabolism of catecholamines in nonneuronal tissues (see Figure 37). 

SELECTIVE MAO-B INHIBITORS Two isozymes of MAO (MAO-A and MAO-B) oxidize monoamines and both are present in the periphery and GI tract MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of dopamine in the brain. At low-to-moderate doses (10 mg/day or less), selegiline (eldepryl) selectively and irreversibly inhibits MAO-B. Unlike nonspecific inhibitors of MAO (e.g., phenelzine, tranylcypromine, isocarboxazid), selegiline does not inhibit peripheral metabolism of catecholamines and can be taken safely with levodopa. Selegihne does not cause the lethal potentiation of indirectly acting sympathomimetic amines such as dietary tyramine. Doses of selegiline higher than 10 mg daily can produce inhibition of MAO-A and should be avoided. 

Aggressive behavior is related to the monoamine neurotransmitters serotonin, dopamine, and noradrenaline. The enzymes monoamine oxidase (MAO) A and B play roles in the metabolism of catecholamines in the brain and peripheral tissues. MAOA degrades dopamine, serotonin, and noradrenaline. 

A. Toxicity results from release of excessive neuronal stores of vasoactive amines, inhibition of metabolism of catecholamines or interacting drugs, or absorption of large amounts of dietary tyramine (which in turn releases catecholamines from neurons). 

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