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Document Page 360 therapy of Parkinson's disease L-dopa (precursor of dopamine) is administered together with a peripheral dopadecarboxylase (DDC) inhibitor (such as carbidopa or benserazide). The major peripheral L-dopa metabolizing enzymes are DDC and COMT. After inhibition of DDC, COMT is responsible for the main catabolism of L-dopa. In the central nervous system COMT together with mono- amino oxidase (MAO) participitates in the metabolism of L-dopa and dopamine. Large amounts of orally administered L-dopa are converted by COMT to 3-O-methyldopa (3-OMD). Having a long plasma halflife (approximately 15 h compared with the dopamine 1-h half-life), 3-OMD accumulates in the plasma during the L-dopa treatment. L-Dopa and 3-OMD also compete for the same active transport system into the brain. It has been proposed that 3-OMD could cause some side effects of the L-dopa treatment (dyskenisia, on-off phenomenon). Inhibition of COMT enzyme decreases the 3-OMD formation and improves the brain entry and bioavailability of L-dopa. The use of COMT inhibition should prolong the L-dopa effects and permit a decreased does [27– 29]. Preclinical and clinical results indicate that both entacapone and tolcapone are orally active, nontoxic and well-tolerated drugs. The adjuvant L- dopa therapy with DDC inhibitor + COMT-inhibitor (+ possible MAO inhibitor) may substitute for the present double therapy in the treatment of Parkinson's disease [27–40]. Together with the development of dopamine agonists and MAO inhibitors, the inhibition of COMT will constitute major progress in the treatment of Parkinson's disease in the near future. B. Other Possible Indications of the COMT Inhibition It has been proposed that COMT inhibitors co-administered with L-dopa could have beneficial effects in the treatment of depressive illness [40]. This can be caused by either the better availability of dopamine or by the elevated noradrenaline levels in the brain. Another hypothesis suggests that the increasing level of AdoMet caused by COMT inhibition may cause an antidepressive effect [33]. Dopamine has also natriuretic and diuretic effects in kidney. There has been evidence that abnormalities of the renal dopamine system can lead to salt- sensitive hypertension [48]. In rat kidney, deamination represents the major pathway in the metabolism of dopamine, but when MAO is inhibited, methylation appears to offer an alternative metabolic pathway [49]. Thus COMT inhibition may be important in the regulation of renal sodium excretion. References 1. Axelrod J, Tomchick R. Enzymatic O-methylation of epinephrine and other catechols. Journal of Biological Chemistry 1958; 233:702–705. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_360.html [4/5/2004 5:30:11 PM]
Document Page 361 2. Guldberg H, Marsden C. Catechol-O-methyl transferase: pharmacological aspects and Physiological role. Pharmacological Reviews 1975; 27:135–206. 3. Rivett AJ, Francis A, Roth JA. Localization of membrane-bound catechol-O- methyltransferase. Journal of Neurochemistry 1983; 40:1494–1496. 4. Karhunen T, Tilgmann C, Ulmanen I, Julkunen I, Panula P. Distribution of catechol-Omethyltransferase enzyme in rat tissues. Journal of Histochemistry and Cytochemistry 1994; 42:1079–1090. 5. Axelrod J. Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacological Reviews 1966; 18:95– 113. 6. Ball P, Knuppen R, Haupt M, Breuer H. Interactions between estrogens and catechol amines III. Studies on the methylation of catechol estrogens, catechol amines and other catechols by the catechol-Omethyltransferase of human liver. Journal of Clinical Endocrinology 1972; 34:736–746. 7. Borchardt RT. N- and O-methylation. In: Jakoby WB, ed. Enzymatic Basis of Detoxification. Vol. 2. New York: Academic Press, 1980:43–62. 8. Nutt JG, Fellman JH. Pharmacokinetics of levodopa. Clinical Neuropharmacology 1984; 7:35–79. 9. Assicot M, Bohuon C. Presence of two distinct catechol-O-methyltransferase activities in red blood cells. Biochimie 1971; 53:871–874. 10. Nissinen E, Männistõ P. Determination of catechol-O-methyltransferase activity by high performance liquid chromatography with electrochemical detection. Analytical Biochemistry 1984; 137:69–73. 11. Salminen M, Lundstrõm K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I. Molecular cloning and characterization of rat liver catechol-O-methyltransferase. Gene 1990; 93:241–247. 12. Tilgmann C, Kalkkinen N. Purification and partial characterization of rat liver soluble catechol-Omethyltransferase. FEBS Letters 1990; 264:95–99. 13. Bertocci B, Garotta G, Da Prada M, et al. Immunoaffinity purification and partial amino acid sequence analysis of catechol-O-methyltransferase from pig liver. Biochimica et Biophysica Acta 1991; 1080:103–109. 14. Lundström K, Salminen M, Jalanko A, Savolainen R, Ulmanen I. Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA and Cell Biology 1991; 10:181–189. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_361.html (1 of 2) [4/5/2004 5:30:23 PM]
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Document Kininogen, 119 high molecu
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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