Catechol-O-methyltransferase, inhibition

Catechol O-methyltransferase inhibition represents therefore a valuable adjuvant to the L-DOPA decarboxylase inhibition. Unfortunately, tolcapone exhibited... 

Lavigne, J.A., Goodman, J.E., Fonong, T., Odwin, S., He, P., Roberts, D.W., and Yager, J.D. (2001) The effects of catechol- O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. Cancer Res., 61, 7488-7494. 

Lu, F., Zahid, M., Saeed, M., Cavalieri, E. L., and Rogan, E. G. (2007) Estrogen metabolism and formation of estrogen-DNA adducts in estradiol-treated MCF-10F cells. The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction and catechol-O-methyltransferase inhibition. J. Steroid Biochem. Mol. Biol. 105, 150-158. 

Catechol O-methyltransferase inhibition therefore represents a valuable adjuvant to L-DOPA decarboxylase... 

A high intracerebral level of S-adenosylhomocysteine may inhibit methylation reactions involving S-adenosyl-methionine. The metabolic repercussions would be extensive, including deficient methylation of proteins and of phos-phatidylethanolamine as well as an inhibition of catechol-O-methyltransferase and histamine-N-methyltransferase. 

Adrenaline and noradrenaline are unstable in aqueous solution where they are subjected to spontaneous oxidation. In vivo this mechanism is only relevant under pathophysiological conditions of an catecholamine excess, since two enzymes, the catechol-O-methyltransferase (COMT) and the monoamineoxidase (MAO), inactivate physiological amounts of the transmitters. There are at least two subtypes of the enzyme MAO, A and B, which can be inhibited selectively for therapeutic purposes, for example by moclobemide and selegiline. 

Entacapone and tolcapon are selective and reversible catechol-O-methyltransferase (COMT) inhibitors which also inhibit the break down of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine. 

Mechanism of Action An antiparkinson agent that inhibits the enzyme catechol-O-methyltransferase (COMT), potentiating dopamine activity and increasing the duration of action of levodopa. Therapeutic Effect Relieves signs and symptoms of Parkinson s disease. 

The figure below illustrates proposed sites of action of drugs. For each drug listed, select the site of action that the drug is most likely to inhibit (a, a receptor p, p receptor COMT, catechol-O-methyltransferase MAO, monoamine oxidase NE, norepinephrine NMN, normetanephrine). 

Piedrafita FJ, Elorriaga C, Fernandez-Alvarez E, Nieto O. Inhibition of catechol- O-methyltransferase by N-(3,4-dihydroxyphenyl) maleimide. Journal of Enzyme Inhibition 1990 4 43-50. 

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. 

Zhu, B.T. and Liehr, J.G., Inhibition of catechol O-methyltransferase-catalyzed O-methyla-tion of 2- and 4-hydroxyestradiol by quercetin. Possible role in estradiol-induced tumorigen-esis, J. Biol. Chem., 271,1357,1996. 

Removal of norepinephrine Norepinephrine may (1) diffuse out of the synaptic space and enter the general circulation, (2) be metabolized to O-methylated derivatives by post-synaptic cell membrane-associated catechol O-methyltransferase (COMT) in the synaptic space, or (3) be recaptured by an uptake system that pulls the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium-potassium activated ATPase that can be inhibited by tricyclic antidepressants such as imipramine (see p. 119), or by cocaine (see Figure 6.3). 

Fig. 3. Schematic representation of the neurochemical events associated with neurotransmitter synthesis, release, re-uptake and metabolism in axons of diencephalic DA neurons terminating in classical synapses (Top Panel), and TIDA neurosecretory neurons terminating in close proximity to the hypophysial portal system (Botton Panel). Arrows with dashed lines represent end-product inhibition of TH activiy by DA (Top + Bottom Panels) or DA presynaptic autoreceptor-mediated inhibition of DA synthesis and release (Top Panel). Abbreviations COMT, Catechol-O-methyltransferase D, dopamine DDC, DOPA decarboxylase DOPA, 3,4-dihydrophenylalanine DOPAC, 3,4-dihydroxyphenylacetic acid HVA, homovanillic acid MAO, monoamine oxidase 3MT, 3-methoxytyramine TH, tyrosine hydroxylase.

Schultz, E. Nissinen, E. Inhibition of rat liver and duodenum soluble catechol-O-methyltransferase by a tight-binding inhibitor OR-462, Biochem. Pharmacol. 1989, 38, 3953-3956. 

Entacapone inhibits catechol-O-methyltransferase (COMT), one of the principal enzymes responsible for the metabolism of dopamine the action of levodopa is thus prolonged. It is most effective for patients with early end-of-dose deterioration, and allows them to take levodopa at 3- or 4-hourly intervals, giving a more predictable and useful response. Entacapone is preferred to long-acting preparations of levodopa whose main disadvantage is their slow onset of action. It can increase the dyskinesias seen in the late stages of Parkinson s disease. 

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). 

Chen D, Wang CY, Lambert JD, Ai N, Welsh WJ, Yang CS. Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites Structure-activity relationship and molecular-modeling studies. Biochem Pharmacol 2005 69 1523-31. 

In a classic paper, Snapper synthesized an ilimaquinone-agarose-affinity resin (30), which was incubated with homogenized bovine liver and then washed extensively.93 Proteins retained by the resin were separated by gel electrophoresis, yielding six main protein bands. Amino acid sequencing of these bands revealed three proteins involved in the activated methyl cycle — SAHase, S-adenosylmethionine synthetase (SAM synthetase), and catechol-O-methyltransferase (COMT) — as well as three unrelated proteins. Subsequent enzymatic assays established that ilimaquinone is a competitive inhibitor of SAHase, but has little effect on the activity of SAM synthetase or COMT. The authors noted that a consequence of SAHase inhibition would be the intracellular accumulation of SAH, which is a potent feedback inhibitor of methyltransferases. These results support the assertion that methylation events play an important role in cellular secretory events and vesicle-mediated processes. The study also highlighted the problem of nonspecific interactions as only one of the six isolated proteins was shown to interact in any way with the natural product. 

Most of the research regarding the antidepressant action of St. John s wort has focused on the hypericins (Wagner and Bladt, 1994). Research has been done to examine the possibility of monoamine oxidase (MAO) or catechol -O-methyltransferase (COMT) inhibition, and inhibition of serotonin and norepinephrine reuptake (Perovic and Muller, 1995 Raffa, 1998). In one study, the effects of hypericum total extract, hypericum fractions, and hypericin on MAO and COMT activity were examined in vitro (Thiede and Walper, 1994). It was concluded that the in vitro concentrations of these preparations required to inhibit MAO were in excess of that attained through ingestion, and thus MAO inhibition could not be an explanation of the herb s antidepressant activity. In addition, COMT inhibition appeared to be associated with flavonols and xanthones rather than hypericins. Another study (Cott, 1997) showed that pure hypericin did not bind to MAO, and confirmed that concentrations of the crude extract required for MAO inhibition exceeded those attained after oral administration. 

Inhibits adenylate cyclase, Na,K-ATPase, catalase, catechol o-methyltransferase, fetredoxin-NADP reductase, glucose-6-P dehydrogenase, lipase, fatty acid oxygenase, peroxidase, cAMP phosphodiesterase, tyrosinase, urea levels. 

Carbidopa inhibits peripheral decarboxylation of levodopa, making more levodopa available for transport to the brain. Levodopa is a precursor of dopamine, which is deficient in parkinsonism patients. Entacapone inhibits the enzyme that metabohzes levodopa (catechol-O-methyltransferase [COMT]), which increases and prolongs levodopa plasma levels. The combination is indicated in the treatment of idiopathic Parkinson disease (1) to substitute (with equivalent strength of each of the 3 immediate-release components) for the previously administered individual products, (2) to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience signs and symptoms of end-of-dose wearing-off (only for patients taking a total daily dose of levodopa of 600 mg or less and not experiencing dyskinesias). 

Alkaloids which inhibit acetylcholine esterase, monoamine oxidase and catechol-O-methyltransferase are tabulated in Table 11. Potent ACE blocker are indole alkaloids of the physostigmine type (e.g., eseramine, geneserine, physovenine, eserine), protoberberine alkaloids (e.g., berberine, columbamine, coptisine, jatrorrhizine, palmatine), steroidal alkaloids (leptine I, solanine, solamargine, and tomatidine), galanthamine and others. A plausible structure-function relationship is not apparent, except that all these alkaloids have a quaternary N under physiological conditions, and that an oxygen can be traced 2 to 4 carbons adjacent to the N, similar to the situation in acetylcholine. 

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