In catecholamine metabolism

Because LCEC had its initial impact in neurochemical analysis, it is not, surprising that many of the early enzyme-linked electrochemical methods are of neurologically important enzymes. Many of the enzymes involved in catecholamine metabolism have been determined by electrochemical means. Phenylalanine hydroxylase activity has been determined by el trochemicaUy monitoring the conversion of tetrahydro-biopterin to dihydrobiopterin Another monooxygenase, tyrosine hydroxylase, has been determined by detecting the DOPA produced by the enzymatic reaction Formation of DOPA has also been monitored electrochemically to determine the activity of L-aromatic amino acid decarboxylase Other enzymes involved in catecholamine metabolism which have been determined electrochemically include dopamine-p-hydroxylase phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase . Electrochemical detection of DOPA has also been used to determine the activity of y-glutamyltranspeptidase The cytochrome P-450 enzyme system has been studied by observing the conversion of benzene to phenol and subsequently to hydroquinone and catechol... 

The two principal en/ymes involved in catecholamine metabolism are monoamine oxida.se (MAO) and catechol-O-methyltransferasc (COMT). Both of these cn/.ymes are distributed throughout the body, with high concentrations found in the liver and kidneys. MAO is ass[Pg.526]

Mescaline causes hallucinogenic effects by stimulating serotonin and dopamine receptors in the central nervous system. The sympathomimetic effects of mescaline are probably also centrally mediated. Changes in catecholamine metabolism and adrenal medullary function may be responsible for the agent s... 

The early pioneering work by Zeller et al. (115) on the potent MAO inhibitory effect of iproniazid—a structural modification of the tuberculostat Isoniazid—and his realization of the physiologic consequences that might arise from such a profound alteration in catecholamine metabolism, the actual confirmation by Brodie, Pletscher, and Shore (27) of the rise in brain monoamine levels following the administration of iproniazid and JB-516 (a-methylphen-ethylhydrazine), and the early euphoric effects noted by Selikoff, Robitzek, and Omstein (96) in tuberculosis patients on iproniazid therapy led Kline and his associates (67) to investigate the possible application of iproniazid in the treatment of mental depression. It was their conclusion that MAO inhibition and antidepressant effect had a causal relationship and that a new approach for the treatment of mental depression had been uncovered. The subject of the MAO inhibitors has been reviewed extensively up to 1960 by Pletscher, Gey, and Zeller (84) and by Biel, Horita, and Drukker (21) to 1963, in comprehensive reviews of the chemistry, biochemistry, pharmacology, clinical application, and structure-activity relationships of the MAO inhibitors. 

Iron deficiency is the most common nutritional cause of anemia in humans. It can result from inadequate iron intake, malabsorption, blood loss, or an increased requirement, as with pregnancy. When severe, it results in a characteristic microcytic, hypochromic anemia. Iron is an essential component of myoglobin heme enzymes such as the cytochromes, catalase, and peroxidase and the metalloflavoprotein enzymes, including xanthine oxidase and the mitochondrial enzyme a-glycerophosphate oxidase. Iron deficiency can affect metabohsm in muscle independent of the effect of anemia on delivery, possibly due to a reduction in the activity of iron-dependent mitochondrial enzymes. Iron deficiency also has been associated with behavioral and learning problems in children, abnormahties in catecholamine metabolism, and impaired heat production. 

A lot of interest in catecholamine metabolism has centred on their metabolic end-products 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and 3-methoxy-4-hydroxyphenylethanol (MHPE). These compounds have been analysed most often as their TFA or PFP derivatives, with electron capture detection for sensitivity. Many different recipes have been published, all variants of the anhydride in ethyl acetate procedure, using different temperatures and reaction times. If 30 minutes at room temperature are sufficient [94], one does not need 40 minutes at 65 °C [95]. Pyridine is not recommended because it gives rise to interference, just as with acetic anhydride (see above). At the end of the reaction the mixture is evaporated to dryness with nitrogen, and the residue is taken up in ethyl acetate. These derivatives are susceptible to hydrolysis, and up to 2% of acetic anhydride may be included in the final solution to protect the derivatives against moisture. 

Measurement of the catecholamines and a variety of the intermediate metabolites in blood or tissue is common in psychiatric and neurochemical research. In clinical chemistry the major interest in catecholamine metabolism surrounds the detection and location of the tumors of neural crest origin -phaeochromocytoma and neuroblastoma. These tumors are fortunately rare but their identification is important because if treated promptly they may be curable. Phaeochromocytoma is associated with secretion of adrenaline and/or noradrenaline into the bloodstream and can either be detected by the increase in the parent compounds or by increased VMA excretion. The most common presentation by the patient is hypertension unresponsive to conventional therapy. Neuroblastoma is the commonest malignant soft tissue tumor of childhood, arising from ectodermal neuroblasts. These tumors secrete abnormally high concentrations of dopamine which is largely metabolized to HVA. 

It is now possible to obtain the catecholamines and many related compounds in a radioactively labelled form. The introduction of liquid-scintillation counting techniques, together with the availability of tritium-labelled compounds of very high specific activities (> 5 Ci/mmole), has been a very important factor in catecholamine research. The use of such radioactively labelled compounds has been critical for the elucidation of the pathways involved in catecholamine metabolism, and has provided the basis for many other recent advances in this field of research. The sensitivity with which tritiated catecholamines can be detected and accurately measured is very high, with a limit of the order of 1 pg (S x 10 moles). 

Saito, S., T. Takagi, T. Koutoku, E.S. Saito, H. Hirakawa, S. Tomonaga, T. Tachibana, D.M. Denbow, and M. Fumse, 2004. Differences in catecholamine metabolism and behaviour in neonatal broiler and layer chicks. Br. Poult. Sci. 45, 158-162. 

Taylor, KM and Laverty, R (1969) The effect of chlordiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of the rat brain. Eur. J. Pharmacol. 8 296-301. 

Propofol infusion syndrome has been described and may result in severe metabolic acidosis, cardiac dysrhythmias, cardiovascular collapse, rhabdomyolysis, and death. The risk may be increased with concomitant catecholamine infusions or when the dose exceeds... 

Tolcapone (Tasmar) and entacapone (Comtan) are used only in conjunction with carbidopa/L-dopa to prevent the peripheral conversion of L-dopa to dopamine (increasing the area under the curve of L-dopa by approximately 35%). Thus, on time is increased by about 1 hour. These agents significantly decrease off time and decrease L-dopa requirements. Concomitant use of nonselective MAO inhibitors should be avoided to prevent inhibition of the pathways for normal catecholamine metabolism. 

Castagnoli N, Jr., Trevor A, Singer TP, et al. Metabolic studies on the nigrostriatal toxin 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridines. In Sandler M, Dahlstrom A, eds. Progress in Catecholamine Research, Part B Central Aspects. New York, NY Alan R. Liss 1988 93-100. 

Disulfoton exposure altered catecholamine levels in animals, and this hormonal imbalance may be associated with elevated acetylcholine levels (Brzezinski 1969, 1972, 1973 Brzezinski and Ludwicki 1973 Brzezinski and Rusiecki 1970 Wysocka-Paruszewska 1970, 1971). In these studies, acute dosing with disulfoton caused increases in urinary and plasma noradrenaline and adrenaline levels, accompanied by decreases of adrenaline in the adrenal glands, in rats. In addition, the major urinary metabolite of catecholamine metabolism, 4-hydroxy-3-methoxymandelic acid (HMMA), was recovered in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1970,... 

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. 

Increased levels of urinary catecholamines may also be associated with accumulation of acetylcholine that resulted from acetylcholinesterase inhibition by disulfoton. No human data were located to support this, but limited animal data provide some evidence. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in rats, respectively, within 72 hours (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). 

Conjugations can also be brought about by sulfotransferases (SULTs) and glutathi-one-S-transferases (GSTs), both of which exist in a number of isoenzymic forms. Amines and alcohols are sulfate acceptors and SULTs are important in steroid hormone and catecholamine metabolism and like the UGTs require the sulfate to be activated prior to its incorporation into the target molecule (Figure 6.32). In this case, sulfate is activated at the expense of two molecules of ATP to form the final sulfate carrier PAPS O -phosphoadenosine-S -phosphosulfate). 

Honma T. 1987. Alteration of catecholamine metabolism in rat brain produced by inhalation exposure to methyl bromide. Jpn J Ind Health 29 218-219. 

Bagdy G, Perenyi A, Frecska E, Seregi A, Fekete MI, Tothfalusi L, Magyar K, Bela A, Arato M. (1988). Effect of adjuvant reserpine treatment on catecholamine metabolism in schizophrenic patients under long-term neuroleptic treatment. J Neural Transm. 71(1) 73-78. 

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. 

Pharmacology Lithium alters sodium transport in nerve and muscle cells, and effects a shift toward intraneuronal catecholamine metabolism. The specific mechanism in mania is unknown, but it affects neurotransmitters associated with affective disorders. Its antimanic effects may be the result of increases in norepinephrine reuptake and increased serotonin receptor sensitivity. Pharmacokinetics ... 

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. 

From the observation that tics were exacerbated by stress, and because cerebrospinal fluid flndings suggested possible alterations in central nervous system catecholamine metabolism, Cohen and colleagues (1979) used clonidine in the treatment of TS in what was among the first theory-based treatments for the disorder. 

Poitou P, Bohuon C Catecholamine metabolism in the rat brain after short and long term hthium administration. J Neurochem 25 535-537, 1975 Pollack MH, Hammerness P Adjunctive yohimbine for treatment of refractory depression. Biol Psychiatry 33 220-221, 1993 Pollack MH, Rosenbaum JF Verapamil in the treatment of recurrent unipolar depression. Biol Psychiatry 22 779-782, 1987... 

Schmidt. M.E., Matochik, J.A., Goldstein, D.S., et al. Gender differences in brain metabolic and plasma catecholamine responses to alpha2-adrenoceptor blockade. 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Metanephrines represent metabolites of the catecholamines urinary levels are greater than total catecholamines but less than those of VMA. In tumors, variations in the metabolic pathways can cause an increase in the metanephrines alone. 

Two important pathways for catecholamine metabolism are O-methylation by COMT, which is cytoplasmically localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the liver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in bigb concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the liver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-57] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is rdatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

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