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In this study, we characterized the enzymology of cytosolic catechol-O-methyltransferase (COMT)-catalyzed …


Biology Articles » Biochemistry » Enzymology » Enzymology of Methylation of Tea Catechins and Inhibition of Catechol-O-methyltransferase by ()-Epigallocatechin Gallate » Introduction

Introduction
- Enzymology of Methylation of Tea Catechins and Inhibition of Catechol-O-methyltransferase by ()-Epigallocatechin Gallate

Green tea has been suggested to have beneficial effects against many diseases including cancer, cardiovascular disease, and Parkinson's disease (Yang and Landau, 2000; Yang et al., 2002). The active constituents and mechanisms involved, however, are not known. (-)-Epigallocatechin gallate (EGCG1) and (-)-epigallocatechin (EGC) are considered to be the major effective constituents of green tea. The bioavailability and biotransformation of tea catechins are not well understood, even though several studies on this topic have been published (Chen et al., 1997; Yang et al., 1998; Li et al., 2001; Meng et al., 2001, 2002). After oral absorption, tea catechins undergo extensive methylation, glucuronidation, and sulfation (Li et al., 2001; Meng et al., 2001). After oral administration of green tea, 4'-O-methyl-EGC (4'-MeEGC) and 4',4"-di-O-methyl-EGCG (4',4"-DiMeEGCG) were detected in the blood and urine samples of humans, mice, and rats (Meng et al., 2001, 2002). The biliary excretion of EGCG methylation products varied with the change of EGCG dosage (Kida et al., 2000; Kohri et al., 2001), suggesting that the methylation of EGCG is dose-dependent.

Studies on the methylation of 30┬ástructurally diverse compounds by human and rat recombinant soluble COMT showed that human and rat soluble COMT had similar substrate selectivity (Lautala et al., 1999). Incubations of catechins with rat liver homogenate and S-adenosylmethionine (SAM) produced 4'-O-methyl-(-)-EGC (4'-MeEGC), 4"-O-methyl-(-)-EGCG (4"-MeEGCG), and 4"-O-methyl-(-)-epicatechin (Okushio et al., 1999). Although the enzymatic methylation of EGCG and EGC has been reported (Lautala et al., 1999; Zhu et al., 2000, 2001), most of these studies used rather high concentrations of EGCG (10-500 ┬ÁM), which were far above the levels achievable in the plasma and tissues after ingesting green tea. The kinetic parameters of EGCG methylation by human liver and the contribution of methylation to the biotransformation of EGCG remain unknown.

COMT is present in both soluble and membrane-bound forms in mammals, with the soluble form predominant in most tissues. COMT catalyzes the O-methylation of various catecholic compounds. The general function of COMT is to eliminate the potentially active or toxic catechol structures of endogenous and exogenous compounds. Methylation decreases the hydrophilicity of catecholic compounds; further sulfation/glucuronidation of the methylated product is usually needed for the effective elimination of the methylation product from the body. COMT has been found in all mammalian tissues investigated, with the highest activity in the liver, then the kidney and gastrointestinal tract. The COMT activity in erythrocytes varies from species to species, high in rats and low in humans (Nissinen et al., 1992; Keranen et al., 1994).

3,4-Dihydroxy-L-phenylalanine (L-DOPA), catecholamines (dopamine, norepinephrine, epinephrine) and catecholestrogens are physiological substrates of COMT. Certain dietary and medicinal products, such as flavonoids, carbidopa, and dihydroxyphenyl serine, are also COMT substrates (Mannisto and Kaakkola, 1999; Lautala et al., 2001). Inhibition of COMT may significantly affect the metabolism of these compounds. Flavonoids are known to inhibit COMT (Gugler and Dengler, 1973). EGCG has been suggested to exhibit a fat-lowering effect through inhibition of COMT, which augments and prolongs norepinephrine-regulated thermogenesis (Dulloo et al., 2000). The inhibition of COMT by EGCG remains to be further characterized.

The present study aims to elucidate the enzymology of methylation of EGCG and EGC by COMT. The species difference among humans, rats, and mice in the methylation of catechins, the effect of glucuronidation on catechin methylation, and the inhibition of COMT activity by EGCG and its metabolites are also investigated.


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