Methyltransferases, inhibition

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

Substrates of COMT include xenobiotics catechols, catecholamines, and catechol estrogens. Three functional classes of chemicals are known to inhibit COMT. S-Adenosyl-I-homocysteine (SAH) is a potent inhibitor of COMT as well as the other SAM-dependent methyltransferases. Inhibition results from SAH binding to the SAM binding site on the enzyme. Certain divalent ions such as Ca+2 and trivalent metal ions such as the salts of lanthanides, neodymium, and europium are excellent inhibitors of COMT. A number of catechol-type substrates such as pyrogallol, fla-vonoids, pyrones, pyridenes, hydroxyquiolines, 3-mercaptotyramine, and tropolones are irreversible inhibitors of COMT. 

Jaspis wondoensis / Poecillastra wondoensis association IC50 = 4.2nM HDAC inhibition 18.6nM DNA methyltransferase inhibition 0.13ug/mL SK-MEL-2 human skin MIC = 4.37ug/mL MRSA... 

Catechol 0-methyltransferase inhibition represents therefore a valuable adjuvant to the 1-DOPA decarboxylase inhibition. Unfortunately, toicapone exhibited severe liver damages and had to be removed from the market. The corresponding vinyiogue entacapone is devoided of these side effects. ... 

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... 

Mahieu P, Buchet J-P, Lauwerys R (1987) Evolution clinique et biologique d une intoxication orale aigue par Tanhydride arsenieux et considerations sur I attitude therapeutique. J Toxicol Clin Exp 7 273-278 Maiorino RM, Aposhian HV (1985) Dimercaptan metal-binding agents influence the biotransformation of arsenite in the rabbit. Toxicol Appl Pharmacol 77 240-250 Marafante E, Vahter M (1984) The effect of methyltransferase inhibition on the metabolism of As]arsenite in mice and rabbits. Chem Biol Interact 50 49-57... 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

Decitabine (5-aza-deoxycytosine) is an analog of the nucleoside 2 -deoxycytidine. It is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and by inhibition of the enzyme DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. DNA hypomethylation is achieved at concentrations below those required to significantly inhibit DNA synthesis, which may promote restoration of function to genes associated with control of cellular differentiation and proliferation. Cytotoxicity in rapidly dividing cells may also result from covalent adducts between DNA methyltransferase and decitabine. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Woodson LC, Ames MM, Selassie CD et al. Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. Mol Pharmacol 1983 24 471-478. 

McBride KL, Gilchrist GS, Smithson WA et al. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inhibited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol 2000 22 441-445. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980 32 651-662. 

Efforts to identify specific inhibitors of histone methyltransferases are in their early stages, and only two specific KMT inhibitors have been identified. The fungal mycotoxin chaetocin (9, Figure 2) inhibits the KMT Su(var)3-9 from Drosophila with an IC50 of 0.8 iM and produces a... 

Transfer of a methyl group from S-adenosylmethionine yields S-adenosylhomocysteine, which potently inhibits several methyltransferases this may partially explain the pathology of homocystinuria. Tissue levels of S-adenosylhomocysteine ordinarily are very low, since this metabolite is rapidly cleaved by a specific hydrolase to homocysteine and adenosine (Fig. 40-4 reaction 3). 

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. 

Harmala alkaloids are inhibitors of brain MAO. Harmane inhibits MAOA in the submicromolar range (5 X 10-7 M) and MAOB in the micromolar range (5 x 10-6 M) (Glover et al. 1982). Harmine inhibits MAOA, but also has additional unspecified monoamine modulatory effects (Meneguz et al. 1994 Fernandez de Arriba et al. 1994). Harmaline or its metabolites may also stimulate aldehyde reductase or catechol 0-methyltransferase (COMT) (Okonmah et al. 1988). 

---