Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids. Metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo.

摘要: Quercetin is highly mutagenic in vitro, yet not carcinogenic when administered chronically at large doses to rodents for 12 months. We hypothesized that catechol-O-methyltransferase-catalyzed O-methylation of quercetin and other catechol-containing flavonoids may provide an efficient inactivation vivo therefore prevent tumor induction by these flavonoids. After one intraperitoneal administration 50 mg/kg hamsters, a urinary ether extract contained 2% 97% 3‘-O-methylquercetin. When the urine was treated first with beta-glucuronidase sulfatase, 13% 87% 3‘-O-methylquercetin were recovered. rapidly O-methylated either porcine liver or hamster kidney catechol-O-methyltransferase, Km values 6.1 6.9 microM Vmax 14,870 200 pmol/mg protein/min, respectively. S-Adenosyl-L-homocysteine exhibited potent feedback inhibition competitive mechanism respect S-adenosyl-L-methionine plus noncompetitive substrate. A comparison rates kinetic characteristics (Km, Vmax, Vmax/Km) demonstrated fisetin up three orders magnitude higher than those catechol estrogens catecholamines. In conclusion, rapid metabolic catalyzed catechol-O-methyltransferase be major reason lack their activities vivo.