Inhibition of NAD(P)H:quinone acceptor oxidoreductase by flavones: a structure-activity study.

A structure-activity study was carried out to determine the important regions of baicalein and oroxylin A, two flavones isolated from the Chinese herb Scutellariae radix, in inhibiting NAD(P)H:quinone acceptor oxidoreductase (EC 1.6.99.2; DT-diaphorase). This quinone reductase is a vitamin K reductase. It is a target for and has been used as a model enzyme to investigate the mode of action of oral anticoagulants. The two flavones were found to inhibit this quinone reductase in nanomolar ranges. The 5-hydroxyl, 7-hydroxyl, 8-hydroxyl, and 2-phenyl groups of these flavones were found to be important for their inhibition of the enzyme. The inhibition profiles of the flavones on the NADH-menadione reductase activity, the NADH-potassium ferricyanide reductase activity, and the NADH-methyl red reductase activity of this enzyme were different. Therefore, even though the flavones were found to be competitive inhibitors with respect to NADH, they probably did not inhibit the enzyme by binding to the nicotinamide nucleotide binding site. Inhibition kinetic studies which indicated that these compounds bound to different sites than those for dicoumarol and phenindone were performed. These results indicate that these flavones are a new type of inhibitor of NAD(P)H:quinone acceptor oxidoreductase and potentially useful as anticoagulant drugs.