CATECHOL-O-METHYLTRANSFERASE-CATALYZED RAPID O-METHYLATION OF MUTAGENIC FLAVONOIDS - METABOLIC INACTIVATION AS A POSSIBLE REASON FOR THEIR LACK OF CARCINOGENICITY IN-VIVO

Quercetin is highly mutagenic in vitro, yet is not carcinogenic when a dministered chronically at large doses to rodents for 12 months. We hy pothesized that catechol-O-methyltransferase-catalyzed O-methylation o f quercetin and other mutagenic catechol-containing flavonoids may pro vide an efficient inactivation in vivo and may therefore prevent tumor induction by these flavonoids. After one intraperitoneal administrati on of 50 mg/kg quercetin to hamsters, a urinary ether extract containe d 2% quercetin and 97% 3'-O-methylquercetin. When the urine was treate d first with bea-glucuronidase and sulfatase, 13% quercetin and 87% 3' -O-methylquercetin were recovered. Quercetin was rapidly O-methylated by either porcine liver or hamster kidney catechol-O-methyltransferase , with K(m) values of 6.1 and 6.9 muM and V(max) values of 14,870 and 200 pmol/mg of protein/min, respectively. S-Adenosyl-L-homocysteine ex hibited a potent feedback inhibition of the catechol-O-methyltransfera se-catalyzed O-methylation of quercetin by a competitive mechanism wit h respect to S-adenosyl-L-methionine and by a competitive plus noncomp etitive mechanism with respect to the substrate. A comparison of the O -methylation rates and kinetic characteristics (K(m), V(max), and V(ma x)/K(m)) demonstrated that rates of O-methylation of quercetin and fis etin were up to three orders of magnitude higher than those of catecho l estrogens and catecholamines. In conclusion, the rapid metabolic ina ctivation of mutagenic flavonoids catalyzed by catechol-O-methyltransf erase may be a major reason for the lack of their carcinogenic activit ies in vivo.